Updated on 2021/12/27

写真a

 
UDONO Heiichiro
 
Organization
Medicine, Dentistry and Pharmaceutical Sciences Professor
Position
Professor
External link

Degree

  • MD

Research Interests

  • 免疫学

  • Immunology

Research Areas

  • Life Science / Cell biology

  • Life Science / Immunology

Education

  • Nagasaki University    

    - 1990

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  • Nagasaki University   医学研究科   病理学専攻

    - 1990

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    Country: Japan

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Research History

  • Okayama University   Graduate School of Medicine, Dentistry and Pharmaceutical Sciences   Professor

    2021.4

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  • Okayama University   Graduate School of Medicine , Dentistry and Pharmaceutical Sciences   Professor

    2011.4 - 2021.3

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  • RIKEN

    2003

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  • Nagasaki University school of medicine, associate professor ., 2003 RIKEN RCAI, Team Leader

    1999

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  • Nagasaki University   Graduate School of Biomedical Sciences

    1999

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Professional Memberships

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Papers

  • Pharmacological effects on anaplerotic pathways alter the metabolic landscape in the tumor microenvironment, causing unpredictable, sustained anti-tumor immunity Invited Reviewed

    Heiichiro Udono, Mikako Nishida

    International Immunology   2021.9

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Oxford University Press (OUP)  

    <title>Abstract</title>
    To achieve sustained anti-tumor immunity, tumor-infiltrating effector CD8 T lymphocytes (CD8 TILs) must be able to produce cytokines, including IFNγ, and proliferate robustly within the local tumor tissue upon antigen recognition. IFNγ production by CD8 TILs depends on glycolysis, whereas their proliferation additionally requires oxidative phosphorylation (OxPhos). The level of OxPhos, and hence the oxygen consumption rate, depends on mitochondrial biogenesis and requires the loading of metabolic precursors into the tricarboxylic acid cycle to keep it functioning. This is referred to as anaplerosis. Recent advances in the field of immuno-metabolism have shown the impact of pharmacological agents on anaplerotic pathways, resulting in metabolic down-regulation in tumor cells; in contrast, the agents trigger sustained anti-tumor immunity by up-regulating both glycolysis and OxPhos in CD8 TILs. The opposing effects of pharmacological inhibition (and/or activation) on anaplerosis in tumor cells and CD8 TILs are unpredictable. Careful dissection of the underlying mechanism might confer important knowledge, helping us to step into a new era for cancer immunotherapy.

    DOI: 10.1093/intimm/dxab067

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  • Mitochondrial reactive oxygen species trigger metformin-dependent antitumor immunity via activation of Nrf2/mTORC1/p62 axis in tumor-infiltrating CD8T lymphocytes Reviewed

    Mikako Nishida, Nahoko Yamashita, Taisaku Ogawa, Keita Koseki, Eiji Warabi, Tomoyuki Ohue, Masaaki Komatsu, Hirokazu Matsushita, Kazuhiro Kakimi, Eiryo Kawakami, Katsuyuki Shiroguchi, Heiichiro Udono

    Journal for ImmunoTherapy of Cancer   9 ( 9 )   e002954 - e002954   2021.9

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:BMJ  

    <sec><title>Background</title>Metformin (Met) is the first-line treatment for type 2 diabetes mellitus and plays an effective role in treating various diseases, such as cardiovascular disease, neurodegenerative disease, cancer, and aging. However, the underlying mechanism of Met-dependent antitumor immunity remains to be elucidated.

    </sec><sec><title>Methods</title>MitoTEMPO, a scavenger of mitochondrial superoxide, abolished the antitumor effect of Met, but not antiprogrammed cell death (PD-1) antibody (Ab) treatment. Consequently, we studied the mechanism of the Met-induced antitumor effect. Expressions of glucose transporter (Glut)-1, mitochondrial reactive oxygen species (mtROS), interferon (IFN)-γ, Ki67, autophagy markers, activation markers for NF-E2-related factor 2 (Nrf2), and mammalian target of rapamaycin complex 1 (mTORC1) in CD8+ tumor-infiltrating T lymphocytes (CD8TILs) were examined by flow cytometry analysis. In addition, conditional knockout mice for Nrf2 and p62 were used to detect these markers, together with the monitoring of in vivo tumor growth. RNA sequencing was performed for CD8TILs and tumor cells. Melanoma cells containing an IFN-γ receptor (IFNγR) cytoplasmic domain deletion mutant was overexpressed and used for characterization of the metabolic profile of those tumor cells using a Seahorse Flux Analyzer.

    </sec><sec><title>Results</title>Met administration elevates mtROS and cell surface Glut-1, resulting in the production of IFN-γ in CD8TILs. mtROS activates Nrf2 in a glycolysis-dependent manner, inducing activation of autophagy, glutaminolysis, mTORC1, and p62/SQSTM1. mTORC1-dependent phosphorylation of p62 at serine 351 (p-p62(S351)) is also involved in activation of Nrf2. Conditional deletion of Nrf2 in CD8TILs abrogates mTORC1 activation and antitumor immunity by Met. In synergy with the effect of anti-PD-1 Ab, Met boosts CD8TIL proliferation and IFN-γ secretion, resulting in decreased glycolysis and oxidative phosphorylation in tumor cells. Consequently, Glut-1 is elevated in CD8TILs, together with the expansion of activated dendritic cells. Moreover, tumor cells lacking in IFNγR signaling abolish IFN-γ production and proliferation of CD8TILs.

    </sec><sec><title>Conclusions</title>We found that Met stimulates production of mtROS, which triggers Glut-1 elevation and Nrf2 activation in CD8TILs. Nrf2 activates mTORC1, whereas mTORC1 activates Nrf2 in a p-p62(S351)-dependent manner, thus creating a feedback loop that ensures CD8TILs’ proliferation. In combination with anti-PD-1 Ab, Met stimulates robust proliferation of CD8TILs and IFN-γ secretion, resulting in an IFN-γ-dependent reprogramming of the tumor microenvironment.

    </sec>

    DOI: 10.1136/jitc-2021-002954

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  • Multifunctionality of CD8+ T cells and PD-L1 expression as a biomarker of anti-PD-1 antibody efficacy in advanced melanoma. Reviewed International journal

    Keiko Manabe, Osamu Yamasaki, Yuki Nakagawa, Tomoko Miyake, Heiichiro Udono, Shin Morizane

    The Journal of dermatology   48 ( 8 )   1186 - 1192   2021.8

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    Anti-programmed cell death protein-1 (PD-1) antibodies have become a standard treatment for advanced melanoma. However, a predictive biomarker for assessing the efficacy of anti-PD-1 antibodies has not been identified. In cancer, CD8+ T cells specific for tumor antigens undergo repeated T-cell receptor stimulation due to the persistence of cancer cells and gradually lose their ability to secrete interleukin 2 (IL-2), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ). We aimed to evaluate multi-cytokine production and immune exhaustion of peripheral CD8+ T cells in melanoma patients treated with anti-PD-1 antibodies. Twenty-four melanoma patients treated with nivolumab were included. Effector cytokine production (IL-2, TNF-α, and IFN-γ) and expression of an exhaustion marker (PD-1) in patients' CD8+ cells were analyzed with flow cytometry. The relationships between parameters such as the neutrophil-to-lymphocyte ratio (NLR) and clinical response to nivolumab were examined. Immunohistochemistry for programmed death-ligand 1 (PD-L1) expression in tumor cells and tumor-infiltrating lymphocytes (TILs) and analysis of their association with clinical response were performed. The clinical response rate to nivolumab was 29%. Regarding TILs, NLR, and several other parameters, no significant difference was found between responders and non-responders. The responder group showed an increase in the percentage of PD-1+ CD8+ /TNF-α+ IFN-γ+ or PD-1+ CD8+ /IFN-γ+ IL-2+ TNF-α+ T cells compared to non-responders. Positivity for PD-L1 expression was significantly higher in the responder group than the non-responder group. In advanced melanoma, the percentage of multifunctional CD8+ PD-1+ T cells and PD-L1 expression in the tumors may be a biomarker for a good response to anti-PD-1 antibody monotherapy.

    DOI: 10.1111/1346-8138.15904

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  • Dysfunction of CD8 + PD-1 + T cells in type 2 diabetes caused by the impairment of metabolism-immune axis Reviewed

    Ichiro Nojima, Shingo Eikawa, Nahoko Tomonobu, Yoshiko Hada, Nobuo Kajitani, Sanae Teshigawara, Satoshi Miyamoto, Atsuhito Tone, Haruhito A. Uchida, Atsuko Nakatsuka, Jun Eguchi, Kenichi Shikata, Heiichiro Udono, Jun Wada

    Scientific Reports   10 ( 1 )   2020.12

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    Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media LLC  

    <title>Abstract</title>
    The metabolic changes and dysfunction in CD8 + T cells may be involved in tumor progression and susceptibility to virus infection in type 2 diabetes (T2D). In C57BL/6JJcl mice fed with high fat-high sucrose chow (HFS), multifunctionality of CD8 + splenic and tumor-infiltrating lymphocytes (TILs) was impaired and associated with enhanced tumor growth, which were inhibited by metformin. In CD8 + splenic T cells from the HFS mice, glycolysis/basal respiration ratio was significantly reduced and reversed by metformin. In the patients with T2D (DM), multifunctionality of circulating CD8 + PD-1 + T cells stimulated with PMA/ionomycin as well as with HLA-A*24:02 CMV peptide was dampened, while metformin recovered multifunctionality. Both glycolysis and basal respiration were reduced in DM, and glycolysis was increased by metformin. The disturbance of the link between metabolism and immune function in CD8 + PD-1 + T cells in T2D was proved by recovery of antigen-specific and non-specific cytokine production via metformin-mediated increase in glycolytic activity.

    DOI: 10.1038/s41598-020-71946-3

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    Other Link: http://www.nature.com/articles/s41598-020-71946-3

  • Berberine improved experimental chronic colitis by regulating interferon-γ- and IL-17A-producing lamina propria CD4+ T cells through AMPK activation Reviewed

    Masahiro Takahara, Akinobu Takaki, Sakiko Hiraoka, Takuya Adachi, Yasuyuki Shimomura, Hiroshi Matsushita, Tien Thi Thuy Nguyen, Kazuko Koike, Airi Ikeda, Shiho Takashima, Yasushi Yamasaki, Toshihiro Inokuchi, Hideaki Kinugasa, Yusaku Sugihara, Keita Harada, Shingo Eikawa, Hidetoshi Morita, Heiichiro Udono, Hiroyuki Okada

    Scientific Reports   9 ( 1 )   2019.12

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media LLC  

    DOI: 10.1038/s41598-019-48331-w

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    Other Link: http://www.nature.com/articles/s41598-019-48331-w

  • Metformin Prevents Peritoneal Dissemination via Immune-suppressive Cells in the Tumor Microenvironment Reviewed International journal

    TAKANORI HIRAYAMA, YASUHIRO NAGATA, MIKAKO NISHIDA, MITSUTOSHI MATSUO, SHINICHIRO KOBAYASHI, AKIRA YONEDA, KENGO KANETAKA, HEIICHIRO UDONO, SUSUMU EGUCHI

    Anticancer Research   39 ( 9 )   4699 - 4709   2019.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Anticancer Research USA Inc.  

    BACKGROUND/AIM: Metformin, a drug for type 2 diabetes, also exerts anticancer effects. This study addressed the immunological effects of metformin on peritoneal dissemination. MATERIALS AND METHODS: We developed a mouse model of peritoneal dissemination via intraperitoneal injection of RLmale1, an X-ray-induced leukemia cell line, into BALB/c mice. Cell-surface markers, cytokine production, and myeloid-derived suppressor cells (MDSCs) were examined in cells from spleen and peritoneal lavage fluid. RESULTS: Metformin-treated mice exhibited suppressed intraperitoneal tumor growth and extended survival, and these effects were lost in mice with severe combined immunodeficiency. MDSCs induction was inhibited in metformin-treated mice. Although MDSC mobilization into the peritoneal cavity was correlated with suppression of interferon-γ production by tumor-infiltrating lymphocytes, the T-helper 1 ability of these lymphocytes was preserved in metformin-treated mice. CONCLUSION: Our findings demonstrate the action of metformin on both intraperitoneal tumors and immune-suppressive cells and might contribute to the development of immunotherapy against peritoneal dissemination.

    DOI: 10.21873/anticanres.13652

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  • Metformin induces CD11b+-cell-mediated growth inhibition of an osteosarcoma: implications for metabolic reprogramming of myeloid cells and anti-tumor effects. Reviewed International journal

    Takenori Uehara, Shingo Eikawa, Mikako Nishida, Yuki Kunisada, Aki Yoshida, Tomohiro Fujiwara, Toshiyuki Kunisada, Toshifumi Ozaki, Heiichiro Udono

    International immunology   31 ( 4 )   187 - 198   2019.3

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    CD11b+ myeloid subpopulations, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), play crucial roles in the suppression of T-cell-mediated anti-tumor immunity. Regulation of these cell types is a primary goal for achieving efficient cancer immunotherapy. We found that metformin (Met) induces CD11b+-cell-mediated growth inhibition of a K7M2neo osteosarcoma independent of T cells, as growth inhibition of K7M2neo was still observed in wild-type (WT) mice depleted of T cells by antibodies and in SCID; this contrasted with the effect of Met on Meth A fibrosarcoma, which was entirely T-cell-dependent. Moreover, the inhibitory effect seen in SCID was abrogated by anti-CD11b antibody injection. PMN-MDSCs were significantly reduced in both spleens and tumors following Met treatment. In TAMs, production of IL-12 and TNF-α, but not IL-10, became apparent, and elevation of MHC class II with reduction of CD206 was observed, indicating a shift from an M2- to M1-like phenotype via Met administration. Metabolically, Met treatment decreased basal respiration and the oxygen consumption rate (OCR)/extracellular acidification rate (ECAR) ratio of CD11b+ cells in tumors, but not in the spleen. In addition, decreased reactive oxygen species (ROS) production and proton leakage in MDSCs and TAMs were consistently observed in tumors. Uptake of both 2-deoxy-2-d-glucose (2-NBDG) and BODIPY® decreased in MDSCs, but only BODIPY® incorporation was decreased in TAMs. Overall, our results suggest that Met redirects the metabolism of CD11b+ cells to lower oxidative phosphorylation (OXPHOS) while elevating glycolysis, thereby pushing the microenvironment to a state that inhibits the growth of certain tumors.

    DOI: 10.1093/intimm/dxy079

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  • Metformin Promotes the Protection of Mice Infected With Plasmodium yoelii Independently of gamma delta T Cell Expansion Reviewed

    Miyakoda Mana, Bayarsaikhan Ganchimeg, Kimura Daisuke, Akbari Masoud, Udono Heiichiro, Yui Katsuyuki

    FRONTIERS IN IMMUNOLOGY   9   2942   2018.12

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    DOI: 10.3389/fimmu.2018.02942

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  • Study Protocol: Phase-Ib Trial of Nivolumab Combined With Metformin for Refractory/Recurrent Solid Tumors. Reviewed International journal

    Toshio Kubo, Takashi Ninomiya, Katsuyuki Hotta, Toshiyuki Kozuki, Shinichi Toyooka, Hiroyuki Okada, Toshiyoshi Fujiwara, Heiichiro Udono, Katsuyuki Kiura

    Clinical lung cancer   19 ( 6 )   e861-e864   2018.11

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    Although immune checkpoint inhibitors have shown significant survival benefits in the treatment of several cancers, optimal outcomes have been limited to certain subsets of patients. In a previous study, we found that the addition of metformin to nivolumab, an anti-programmed cell death protein 1 (PD-1) antibody, yielded substantial tumor regression in mouse models. Further analysis revealed that the number of tumor-infiltrating CD8 T cells had increased markedly. Based on this result, we have launched an investigator-initiated open-label phase-Ib clinical trial. The objectives of this trial are to investigate the safety, efficacy, and pharmacokinetics of a metformin-nivolumab combination treatment. This study consists of 2 parts. The recommended dose of metformin combined with nivolumab is determined in part 1. The safety and efficacy of the optimal dose of metformin to be delivered in conjunction with nivolumab are examined in part 2. Patient eligibility is based on the following criteria: pathologic diagnosis of refractory/recurrent solid tumor (part 1), and non-small-cell lung cancer or pancreatic cancer refractory to standard primary treatment (part 2); no prior use of immune checkpoint inhibitor; performance status 0 or 1; age ≥ 20 years; and adequate organ function. The primary endpoints are safety in part 1 and safety and pharmacokinetics in part 2. The maximum tolerated dose and recommended dose are determined in part 1 by the 3 + 3 cohort method, and the dose-limiting toxicity evaluation period for each patient is 4 weeks from the start of administration. In part 2, metformin is administered at the optimal dose determined in part 1. Total enrollment is 9 to 18 patients for part 1 and 30 patients for part 2. Enrollment began in 2017, and will be completed by 2019. The University Hospital Medical Information Network registration number for this study is 000028405.

    DOI: 10.1016/j.cllc.2018.07.010

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  • Extracellular and Non-Chaperone Function of Heat Shock Protein−90α Is Required for Skin Wound Healing Reviewed

    Ayesha Bhatia, Kathryn O’Brien, Jiacong Guo, Vadim Lincoln, Chiaki Kajiwara, Mei Chen, David T. Woodley, Heiichiro Udono, Wei Li

    Journal of Investigative Dermatology   138 ( 2 )   423 - 433   2018.2

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    DOI: 10.1016/j.jid.2017.08.043

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  • Metformin Mediates Protection against Legionella Pneumonia through Activation of AMPK and Mitochondrial Reactive Oxygen Species Reviewed

    Chiaki Kajiwara, Yu Kusaka, Soichiro Kimura, Tetsuo Yamaguchi, Yuta Nanjo, Yoshikazu Ishii, Heiichiro Udono, Theodore J. Standiford, Kazuhiro Tateda

    Journal of Immunology   200 ( 2 )   623 - 631   2018.1

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:American Association of Immunologists  

    In Legionella pneumophila infection, macrophages play a critical role in the host defense response. Metformin, an oral drug for type 2 diabetes, is attracting attention as a new supportive therapy against a variety of diseases, such as cancer and infectious diseases. The novel mechanisms for metformin actions include modulation of the effector functions of macrophages and other host immune cells. In this study, we have examined the effects of metformin on L. pneumophila infection in vitro and in vivo. Metformin treatment suppressed growth of L. pneumophila in a time- and concentration-dependent fashion in bone marrow-derived mac-rophages, RAW cells (mouse), and U937 cells (human). Metformin induced phosphorylation of AMP-activated protein kinase (AMPK) in L. pneumophila-infected bone marrow-derived macrophages, and the AMPK inhibitor Compound C negated metformin-mediated growth suppression. Also, metformin induced mitochondrial reactive oxygen species but not phagosomal NADPH oxidase-derived reactive oxygen species. Metformin-mediated growth suppression was mitigated in the presence of the reactive oxygen species scavenger glutathione. In a murine L. pneumophila pneumonia model, metformin treatment improved survival of mice, which was associated with a significant reduction in bacterial number in the lung. Similar to in vitro observations, induction of AMPK phosphorylation and mitochondrial ROS was demonstrated in the infected lungs of mice treated with metformin. Finally, glutathione treatment abolished metformin effects on lung bacterial clearance. Collectively, these data suggest that metformin promotes mitochondrial ROS production and AMPK signaling and enhances the bactericidal activity of macro-phages, which may contribute to improved survival in L. pneumophila pneumonia.

    DOI: 10.4049/jimmunol.1700474

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  • Attenuation of CD4+ CD25+ Regulatory T Cells in the Tumor Microenvironment by Metformin, a Type 2 Diabetes Drug Reviewed

    Yuki Kunisada, Shingo Eikawa, Nahoko Tomonobu, Shohei Domae, Takenori Uehara, Shohei Hori, Yukihiro Furusawa, Koji Hase, Akira Sasaki, Heiichiro Udono

    EBioMedicine   25   154 - 164   2017.11

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    Authorship:Last author, Corresponding author   Publishing type:Research paper (scientific journal)  

    CD4+ CD25+ regulatory T cells (Treg), an essential subset for preventing autoimmune diseases, is implicated as a negative regulator in anti-tumor immunity. We found that metformin (Met) reduced tumor-infiltrating Treg (Ti-Treg), particularly the terminally-differentiated CD103+ KLRG1+ population, and also decreased effector molecules such as CTLA4 and IL-10. Met inhibits the differentiation of naïve CD4+ T cells into inducible Treg (iTreg) by reducing forkhead box P3 (Foxp3) protein, caused by mTORC1 activation that was determined by the elevation of phosphorylated S6 (pS6), a downstream molecule of mTORC1. Rapamycin and compound C, an inhibitor of AMP-activated protein kinase (AMPK) restored the iTreg generation, further indicating the involvement of mTORC1 and AMPK. The metabolic profile of iTreg, increased Glut1-expression, and reduced mitochondrial membrane-potential and ROS production of Ti-Treg aided in identifying enhanced glycolysis upon Met-treatment. The negative impact of Met on Ti-Treg may help generation of the sustained antitumor immunity.

    DOI: 10.1016/j.ebiom.2017.10.009

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  • Mapping the Interactome of a Major Mammalian Endoplasmic Reticulum Heat Shock Protein 90 Reviewed

    Feng Hong, Saleh Mohammad Rachidi, Debbie Lundgren, David Han, Xiu Huang, Hongyu Zhao, Yayoi Kimura, Hisashi Hirano, Osamu Ohara, Heichiiro Udono, Songdong Meng, Bei Liu, Zihai Li

    PLOS ONE   12 ( 1 )   e0169260 - e0169260   2017.1

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    DOI: 10.1371/journal.pone.0169260

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  • Study about the Efficacy of Metformin to Immune Function in Cancer Patients Reviewed

    Watanabe Mototsugu, Yamamoto Hiromasa, Eikawa Shingo, Shien Kazuhiko, Shien Tadahiko, Soh Junichi, Hotta Katsuyuki, Wada Jun, Hinotsu Shiro, Fujiwara Toshiyoshi, Kiura Katsuyuki, Doihara Hiroyoshi, Miyoshi Shinichiro, Udono Heiichiro, Toyooka Shinichi

    Acta Medica Okayama   70 ( 4 )   327 - 330   2016.8

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    Language:English   Publisher:Okayama University Medical School  

    DOI: 10.18926/AMO/54514

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  • The induction of antigen-specific CTL by in situ Ad-REIC gene therapy Reviewed

    2016.2

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  • Hsp90 and ECM29 Are Important to Maintain the Integrity of Mammalian 26S Proteasome Reviewed

    2015.12

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  • Phase Ia Study of FoxP3(+) CD4 Treg Depletion by Infusion of a Humanized Anti-CCR4 Antibody, KW-0761, in Cancer Patients Reviewed

    Koji Kurose, Yoshihiro Ohue, Hisashi Wada, Shinsuke Iida, Takashi Ishida, Takashi Kojima, Toshihiko Doi, Susumu Suzuki, Midori Isobe, Takeru Funakoshi, Kazuhiro Kakimi, Hiroyoshi Nishikawa, Heiichiro Udono, Mikio Oka, Ryuzo Ueda, Eiichi Nakayama

    CLINICAL CANCER RESEARCH   21 ( 19 )   4327 - 4336   2015.10

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:AMER ASSOC CANCER RESEARCH  

    Purpose: FoxP3(+) Tregs inhibit immune responses against tumors. KW-0761 is a humanized anti-human CCR4 monoclonal antibody (mAb) that has antibody-dependent cellular cytotoxicity activity. Depletion of CCR4-expressing FoxP3(+) CD4 Tregs by KW-0761 infusion was investigated in solid cancer patients.
    Experimental Design: We conducted a phase Ia clinical trial of KW-0761 infusion in 7 lung and 3 esophageal cancer patients. Toxicity, clinical efficacy, changes in lymphocyte subpopulations, including Tregs, and induction of immune responses were analyzed.
    Results: The results showed that KW-0761 infusion in a dose range between0.1mg/kg and 1.0mg/kgwas safe andwell tolerated. Nodose-limiting toxicitywas observed. Four of 10 patients showed stable disease during treatment and were long survivors. The monitoring of FoxP3(+) Tregs in the peripheral blood mononuclear cells during treatment indicated efficient depletion of those cells, even at the lowest dose of 0.1 mg/kg used. The reduction in Th 1 CD4 T cells and CD8 T cells was limited, whereas a significant reduction was observed with Th 2 and Th 17 CD4 T cells. Immune responses to cancer/testis (CT) antigens and an autoantibody response to thyroid peroxidase were observed in some patients.
    Conclusions: The findings showed Tregs depletion and the possible occurrence of an immune response following KW-0761 infusion. Combined use of KW-0761 to deplete FoxP3(+) Tregs with other immunotherapies, such as cancer vaccines or checkpoint inhibitors, is a promising approach to augment immune responses. (C) 2015 AACR.

    DOI: 10.1158/1078-0432.CCR-15-0357

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  • Detection and Tracking of NY-ESO-1-Specific CD8+ T Cells by High-Throughput T Cell Receptor β (TCRB) Gene Rearrangements Sequencing in a Peptide-Vaccinated Patient Reviewed

    Manami Miyai, Shingo Eikawa, Akihiro Hosoi, Tamaki Iino, Hirokazu Matsushita, Midori Isobe, Akiko Uenaka, Heiichiro Udono, Jun Nakajima, Eiichi Nakayama, Kazuhiro Kakimi

    PLOS ONE   10 ( 8 )   e0136086 - e0136086   2015.8

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    DOI: 10.1371/journal.pone.0136086

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  • Immune-mediated antitumor effect by type 2 diabetes drug, metformin Reviewed

    Shingo Eikawa, Mikako Nishida, Shusaku Mizukami, Chihiro Yamazaki, Eiichi Nakayama, Heiichiro Udono

    Proceedings of the National Academy of Sciences of the United States of America   112 ( 6 )   1809 - 1814   2015.2

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    Metformin, a prescribed drug for type 2 diabetes, has been reported to have anti-cancer effects; however, the underlying mechanism is poorly understood. Here we show that this mechanism may be immune-mediated. Metformin enabled normal but not T-cell-deficient SCID mice to reject solid tumors. In addition, it increased the number of CD8+ tumor-infiltrating lymphocytes (TILs) and protected them from apoptosis and exhaustion characterized by decreased production of IL-2, TNFα, and IFNγ. CD8+ TILs capable of producing multiple cytokines were mainly PD-1-Tim-3+, an effector memory subset responsible for tumor rejection. Combined use of metformin and cancer vaccine improved CD8+ TIL multifunctionality. The adoptive transfer of antigen-specific CD8+ T cells treated with metformin concentrations as low as 10 μM showed efficient migration into tumors while maintaining multifunctionality in a manner sensitive to the AMP-activated protein kinase (AMPK) inhibitor compound C. Therefore, a direct effect of metformin on CD8+ T cells is critical for protection against the inevitable functional exhaustion in the tumor microenvironment.

    DOI: 10.1073/pnas.1417636112

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  • Immunotherapy for Bone and Soft Tissue Sarcomas Reviewed

    Takenori Uehara, Tomohiro Fujiwara, Ken Takeda, Toshiyuki Kunisada, Toshifumi Ozaki, Heiichiro Udono

    BIOMED RESEARCH INTERNATIONAL   2015   2015

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    Although multimodal therapies including surgery, chemotherapy, and radiotherapy have improved clinical outcomes of patients with bone and soft tissue sarcomas, the prognosis of patients has plateaued over these 20 years. Immunotherapies have shown the effectiveness for several types of advanced tumors. Immunotherapies, such as cytokine therapies, vaccinations, and adoptive cell transfers, have also been investigated for bone and soft tissue sarcomas. Cytokine therapies with interleukin-2 or interferons have limited efficacy because of their cytotoxicities. Liposomal muramyl tripeptide phosphatidylethanolamine (L-MTP-PE), an activator of the innate immune system, has been approved as adjuvant therapeutics in combination with conventional chemotherapy in Europe, which has improved the 5-year overall survival of patients. Vaccinations and transfer of T cells transduced to express chimeric antigen receptors have shown some efficacy for sarcomas. Ipilimumab and nivolumab are monoclonal antibodies designed to inhibit immune checkpoint mechanisms. These antibodies have recently been shown to be effective for patients with melanoma and also investigated for patients with sarcomas. In this review, we provide an overview of various trials of immunotherapies for bone and soft tissue sarcomas, and discuss their potential as adjuvant therapies in combination with conventional therapies.

    DOI: 10.1155/2015/820813

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  • HSP90α plays an important role in piRNA biogenesis and retrotransposon repression in mouse Reviewed International journal

    Tomoko Ichiyanagi, Kenji Ichiyanagi, Ayako Ogawa, Satomi Kuramochi-Miyagawa, Toru Nakano, Shinichiro Chuma, Hiroyuki Sasaki, Heiichiro Udono

    Nucleic Acids Research   42 ( 19 )   11903 - 11911   2014.10

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    HSP90, found in all kingdoms of life, is a major chaperone protein regulating many client proteins. We demonstrated that HSP90α, one of two paralogs duplicated in vertebrates, plays an important role in the biogenesis of fetal PIWI-interacting RNAs (piRNA), which act against the transposon activities, in mouse male germ cells. The knockout mutation of Hsp90α resulted in a large reduction in the expression of primary and secondary piRNAs and mislocalization of MIWI2, a PIWI homolog. Whereas the mutation in Fkbp6 encoding a co-chaperone reduced piRNAs of 28-32 nucleotides in length, the Hsp90α mutation reduced piRNAs of 24-32 nucleotides, suggesting the presence of both FKBP6-dependent and -independent actions of HSP90α. Although DNA methylation and mRNA levels of L1 retrotransposon were largely unchanged in the Hsp90α mutant testes, the L1-encoded protein was increased, suggesting the presence of post-transcriptional regulation. This study revealed the specialized function of the HSP90α isofom in the piRNA biogenesis and repression of retrotransposons during the development of male germ cells in mammals.

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  • Vaccination With NY- ESO-1 Overlapping Peptides Mixed With Picibanil OK-432 and Montanide ISA-51 in Patients With Cancers Expressing the NY- ESO-1 Antigen Reviewed

    Hisashi Wada, Midori Isobe, Kazuhiro Kakimi, Yu Mizote, Shingo Eikawa, Eiichi Sato, Nagio Takigawa, Katsuyuki Kiura, Kazuhide Tsuji, Keiji Iwatsuki, Makoto Yamasaki, Hiroshi Miyata, Hirokazu Matsushita, Heiichiro Udono, Yasuyuki Seto, Kazuhiro Yamada, Hiroyoshi Nishikawa, Linda Pan, Ralph Venhaus, Mikio Oka, Yuichiro Doki, Eiichi Nakayama

    JOURNAL OF IMMUNOTHERAPY   37 ( 2 )   84 - 92   2014.2

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    We conducted a clinical trial of an NY-ESO-1 cancer vaccine using 4 synthetic overlapping long peptides (OLP; peptides #1, 79-108; #2, 100-129; #3, 121-150; and #4, 142-173) that include a highly immunogenic region of the NY-ESO-1 molecule. Nine patients were immunized with 0.25 mg each of three 30-mer and a 32-mer long NY-ESO-1 OLP mixed with 0.2 KE Picibanil OK-432 and 1.25 mL Montanide ISA-51. The primary endpoints of this study were safety and NY-ESO-1 immune responses. Five to 18 injections of the NY-ESO-1 OLP vaccine were well tolerated. Vaccine-related adverse events observed were fever and injection site reaction (grade 1 and 2). Two patients showed stable disease after vaccination. An NY-ESO-1-specific humoral immune response was observed in all patients and an antibody against peptide #3 (121-150) was detected firstly and strongly after vaccination. NY-ESO-1 CD4 and CD8 T-cell responses were elicited in these patients and their epitopes were identified. Using a multifunctional cytokine assay, the number of single or double cytokine-producing cells was increased in NY-ESO-1-specific CD4 and CD8 T cells after vaccination. Multiple cytokine-producing cells were observed in PD-1 (-) and PD-1 (+) CD4 T cells. In conclusion, our study indicated that the NY-ESO-1 OLP vaccine mixed with Picibanil OK-432 and Montanide ISA-51 was well tolerated and elicited NY-ESO-1-specific humoral and CD4 and CD8 T-cell responses in immunized patients.

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  • Monitoring multifunctionality of immune-exhausted CD8 T cells in cancer patients. Invited Reviewed International journal

    Shingo Eikawa, Shusaku Mizukami, Heiichiro Udono

    Methods in molecular biology (Clifton, N.J.)   1142   11 - 7   2014

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    CD8 T cells play a critical role in the host defense against cancers and infectious diseases. However, the presence of antigen-specific CD8 T cells does not always imply that cancers and/or pathogens are efficiently eliminated in the body. Concerning this point, the recent studies suggest the concept of immune exhaustion of CD8 T cells, characterized by their decreased production of IL-2, TNFα, and IFNγ even after antigen stimulation. Thus, continuous stimulation of CD8 T cells by the persistent antigens results in immune exhaustion, which eventually causes immune tolerance against cancers and chronic infections. The identification of immune effector and/or exhausted CD8 T cells by monitoring multiple parameters including T cell exhaustion markers such as PD-1 and Tim-3 and intracellular cytokines is, therefore, crucial to understand the real-time, ongoing immune status. For this purpose, polychromatic flow cytometry is the most common and reliable tool to monitor T cell functions. We describe here the method for detection of immune-exhaustion status of CD8 T cells from human peripheral blood mononuclear cells (PBMCs). By stimulation of PBMCs with PMA/ionomycin for 6 h, more than 1-2 % of total CD8 T cells are identified as positive in terms of multifunctionality, thus producing multiple cytokines--IL-2, TNFα, and IFNγ--at single-cell level in case of all healthy donors. By contrast, CD8 T cells from certain populations of cancer patients are significantly less effective; less than 0.5 % of CD8 T cells are positive in producing such multiple cytokines. The cutoff value around 0.5 % of CD8 T cells might distinguish patients who would receive beneficial effect by cancer vaccine from those who would not respond to the vaccine. Thus, the remaining capacity to produce multiple cytokines of CD8 T cells might be a critical parameter determining the outcome of cancer patients who receive various kinds of cancer vaccines. The method to monitor the state of multifunctionality of CD8 T cells, as described here, would become more important to understand the immune statues in cancers and chronic infectious diseases such as AIDS and malaria infections.

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  • Induction of CD8 T-cell responses restricted to multiple HLA class I alleles in a cancer patient by immunization with a 20-mer NY-ESO-1f (NY-ESO-1 91-110) peptide Reviewed

    Shingo Eikawa, Kazuhiro Kakimi, Midori Isobe, Kiyotaka Kuzushima, Immanuel Luescher, Yoshihiro Ohue, Kazuhiro Ikeuchi, Akiko Uenaka, Hiroyoshi Nishikawa, Heiichiro Udono, Mikio Oka, Eiichi Nakayama

    INTERNATIONAL JOURNAL OF CANCER   132 ( 2 )   345 - 354   2013.1

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    Immunogenicity of a long 20-mer NY-ESO-1f peptide vaccine was evaluated in a lung cancer patient TK-f01, immunized with the peptide with Picibanil OK-432 and Montanide ISA-51. We showed that internalization of the peptide was necessary to present CD8 T-cell epitopes on APC, contrasting with the direct presentation of the short epitope. CD8 T-cell responses restricted to all five HLA class I alleles were induced in the patient after the peptide vaccination. Clonal analysis showed that B*35:01 and B*52:01-restricted CD8 T-cell responses were the two dominant responses. The minimal epitopes recognized by A*24:02, B*35:01, B*52:01 and C*12:02-restricted CD8 T-cell clones were defined and peptide/HLA tetramers were produced. NY-ESO-1 91-101 on A*24:02, NY-ESO-1 92-102 on B*35:01, NY-ESO-1 96-104 on B*52:01 and NY-ESO-1 96-104 on C*12:02 were new epitopes first defined in this study. Identification of the A*24:02 epitope is highly relevant for studying the Japanese population because of its high expression frequency (60%). High affinity CD8 T-cells recognizing tumor cells naturally expressing the epitopes and matched HLA were induced at a significant level. The findings suggest the usefulness of a long 20-mer NY-ESO-1f peptide harboring multiple CD8 T-cell epitopes as an NY-ESO-1 vaccine. Characterization of CD8 T-cell responses in immunomonitoring using peptide/HLA tetramers revealed that multiple CD8 T-cell responses comprised the dominant response.

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  • HSP90 alpha deficiency does not affect immunoglobulin gene hypermutation and class switch but causes enhanced MHC class II antigen presentation Reviewed

    Yingqian Li, Shuyin Li, Mari Hoshino, Rikiya Ishikawa, Chiaki Kajiwara, Xiang Gao, Yaofeng Zhao, Satoshi Ishido, Heiichiro Udono, Ji-Yang Wang

    INTERNATIONAL IMMUNOLOGY   24 ( 12 )   751 - 758   2012.12

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    Heat shock protein 90 (HSP90) is a molecular chaperone required for efficient antigen presentation and cross-presentation. In addition, HSP90 was recently reported to interact with and stabilize the activation-induced cytidine deaminase (AID) and plays a critical role in immunoglobulin gene hypermutation and class switch recombination. In mice and humans, there are two HSP90 isoforms, HSP90 and HSP90, but the in vivo role of each isoform remains largely unknown. Here we have analyzed humoral immune responses in HSP90-deficient mice. We found that HSP90 deficiency did not affect AID protein expression. B cell development and maturation, as well as immunoglobulin gene hypermuation and class switch, occurred normally in HSP90-deficient mice. However, antibody production to a T-dependent antigen was elevated in the mutant mice and this was associated with enhanced MHC class II antigen presentation to T helper cells by dendritic cells. Our results reveal a previously unidentified inhibitory role for HSP90 isoform in MHC class II antigen presentation and the humoral immune response. Along with our recent finding that HSP90 is required for antigen cross-presentation, these results suggest that HSP90 controls the balance of humoral and cellular immunity by dictating the fate of presentation of exogenous antigen.

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  • Phenotypic analysis of monocyte-derived dendritic cells loaded with tumor antigen with heat-shock cognate protein-70 Reviewed

    Shinichiro Ito, Yasuhiro Nagata, Seiya Susumu, Akira Yoneda, Mitsutoshi Matsuo, Katsuyuki Yui, Heiichiro Udono, Susumu Eguchi, Takashi Kanematsu

    Anticancer Research   32   4897 - 4904   2012.11

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    Background/Aim: The cross-presentation system of tumor antigen by monocyte-derived dendritic cells (mo-DCs) has been observed under appropriate conditions. Both CD14- negative and CD1a-positive phenotypes were critical in our previous study. This study compared the phenotype of mo-DCs and identified the conditions that favored T helper-1 (Th1) cytokine production after stimulation with the hsc70 and NY-ESO- 1 p157-165 epitope fusion protein (hsc70/ESO p157- 165). Materials and Methods: The mo-DCs were induced from healthy donors. Their surface markers and cytokine production were examined after stimulation with hsc70/ESO p157-165. Results: CD1a+ and CD1a- mo-DCs were generated in half of the healthy donors. The concentration of fetal calf serum in the culture medium was critical for the induction of CD1a+ DCs, which were able to produce interleukin-12 (IL-12), but not IL-10. Neutralizing IL-6 and IL-6R antibodies affected the expression of CD1a. Conclusion: Anti IL-6 analogs may be effective adjuvants for the development of mo-DC-based cancer vaccine.

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  • Spermatogenesis arrest caused by conditional deletion of Hsp90α in adult mice Reviewed

    Chiaki Kajiwara, Shiho Kondo, Shizuha Uda, Lei Dai, Tomoko Ichiyanagi, Tomoki Chiba, Satoshi Ishido, Takehiko Koji, Heiichiro Udono

    Biology Open   1 ( 10 )   977 - 982   2012.10

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    <title>Summary</title>
    It is controversial whether a functional androgen receptor (AR) on germ cells, including spermatogonia, is essential for their development into sperm and, thus, initiation and maintenance of spermatogenesis. It was recently shown that many spermatocytes underwent apoptosis in the testes of Hsp90α KO mice. We had generated Hsp90α KO mice independently and confirmed this phenotype. However, the important question of whether Hsp90α is required to maintain spermatogenesis in adult mice in which testicular maturation is already completed could not be addressed using these conventional KO mice. To answer this question, we generated a tamoxifen-inducible deletion mutant of Hsp90α and found that conditional deletion of Hsp90α in adult mice caused even more severe apoptosis in germ cells beyond the pachytene stage, leading to complete arrest of spermatogenesis and testicular atrophy. Importantly, immunohistochemical analysis revealed that AR expression in WT testis was more evident in spermatogonia than in spermatocytes, whereas its expression was aberrant and ectopic in Hsp90α KO testis, raising the possibility that an AR abnormality in primordial germ cells is involved in spermatogenesis arrest in the Hsp90α KO mice. Our results suggest that the AR, specifically chaperoned by Hsp90α in spermatogonia, is critical for maintenance of established spermatogenesis and for survival of spermatocytes in adult testis, in addition to setting the first wave of spermatogenesis before puberty.

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  • [Heat shock protein and antigen cross-presentation].

    Heiichiro Udono

    Seikagaku. The Journal of Japanese Biochemical Society   84 ( 10 )   829 - 39   2012.10

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  • Differential MyD88/IRAK4 requirements for cross-priming and tumor rejection induced by heat shock protein 70-model antigen fusion protein. International journal

    Shusaku Mizukami, Chiaki Kajiwara, Masato Tanaka, Tsuneyasu Kaisho, Heiichiro Udono

    Cancer science   103 ( 5 )   851 - 9   2012.5

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    Priming of CD8(+) T cells requires two signals, one produced by T-cell receptor recognition of antigen, and a second that is often provided by the innate immune response. In this context, antigens non-covalently or covalently associated with heat shock proteins (HSP) are internalized and processed in antigen-presenting cells (APC) to be presented by MHC I molecules to CD8(+) T cells, thus, signal 1 has been well characterized in this pathway of cross-presentation. Signal 2 is not fully understood, although there are reports that Toll-like receptors (TLRs) interact with HSP and activate APC. The ability of HSP to activate APC through TLRs is, however, controversial because of the possibility of endotoxin contamination. Using a variety of TLR KO mice, we present evidence that TLRs (TLR2, 3, 4, 7, and 9) and their adaptor molecules MyD88 and IRAK4 are dispensable in cross-priming by a mycobacterial HSP70-antigen (ovalbumin as a model antigen) fusion protein; in contrast, MyD88/IRAK4, but not TLRs, are required for tumor rejection induced by the same reagent. Our results indicate that HSP-mediated cross-priming uses a second signal produced by mechanisms other than TLR cascades. We hypothesize that efficient cross-priming by HSP70 alone is insufficient for tumor rejection and that MyD88/IRAK4-dependent inflammatory stimulation, which might contribute to maintenance of the initially primed effector cells, is required to eradicate tumor burden.

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  • Heat Shock Protein Magic in Antigen Trafficking within Dendritic Cells:Implications in Antigen Cross-presentation in Immunity Invited Reviewed

    Acta Medica Okayama   66 ( 1 )   1 - 6   2012.2

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    DOI: 10.18926/AMO/48075

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  • HSP70 and HSP90 Differentially Regulate Translocation of Extracellular Antigen to the Cytosol for Cross-Presentation. International journal

    Yu Kato, Chiaki Kajiwara, Ikuo Ishige, Shusaku Mizukami, Chihiro Yamazaki, Shingo Eikawa, Kazuhiro Kakimi, Heiichiro Udono

    Autoimmune diseases   2012   745962 - 745962   2012

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    Antigens (Ag) from cancer or virus-infected cells must be internalized by dendritic cells (DCs) to be presented to CD8(+) T cells, which eventually differentiate into Ag-specific cytotoxic T lymphocytes (CTLs) that destroy cancer cells and infected cells. This pathway is termed cross-presentation and is also implicated as an essential step in triggering autoimmune diseases such as Type I diabetes. Internalized Ag locates within endosomes, followed by translocation through a putative pore structure spanning endosomal membranes into the cytosol, where it is degraded by the proteasome to generate antigen peptides. During translocation, Ag is believed to be unfolded since the pore size is too narrow to accept native Ag structure. Here, we show that paraformaldehyde-fixed, structurally inflexible Ag is less efficient in cross-presentation because of diminished translocation into the cytosol, supporting the "unfolded Ag" theory. We also show that HSP70 inhibitors block both endogenous and cross-presentation. ImageStream analysis revealed that the inhibition in cross-presentation is not due to blocking of Ag translocation because a HSP70 inhibitor rather facilitates the translocation, which is in marked contrast to the effect of an HSP90 inhibitor that blocks Ag translocation. Our results indicate that Ag translocation to the cytosol in cross-presentation is differentially regulated by HSP70 and HSP90.

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  • Heat shock protein 90 (HSP90) contributes to cytosolic translocation of extracellular antigen for cross-presentation by dendritic cells Reviewed International journal

    IMAI Takashi, KATO Yu, KAJIWARA Chiaki, MIZUKAMI Shusaku, ISHIGE Ikuo, ICHIYANAGI Tomoko, HIKIDA Masaki, WANG Ji‐Yang, UDONO Heiichiro

    Proc Natl Acad Sci USA   108 ( 39 )   16363 - 16368   2011.9

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    In antigen (Ag) cross-presentation, dendritic cells (DCs) take up extracellular Ag and translocate them from the endosome to the cytosol for proteasomal degradation. The processed peptides can enter the conventional MHC I pathway. The molecules responsible for the translocation of Ag across the endosomal membrane into the cytosol are unknown. Here we demonstrate that heat shock protein 90 (HSP90) is critical for this step. Cross-presentation and -priming were decreased in both HSP90α-null DCs and mice. CD8α(+) DC apoptosis mediated by translocation of exogenous cytochrome c to the cytosol was also eliminated in HSP90α-null mice. Ag translocation into the cytosol was diminished in HSP90α-null DCs and in DCs treated with an HSP90 inhibitor. Internalized Ag was associated with HSP90 and translocated to the cytosol, a process abrogated by the HSP90 inhibitor. Ag within purified phagosomes was released in an HSP90-dependent manner. These results demonstrate the important role of HSP90 in cross-presentation by pulling endosomal Ag out into the cytosol.

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  • Essential Role of Endogenous Heat Shock Protein 90 of Dendritic Cells in Antigen Cross-Presentation Reviewed International journal

    Ichiyanagi Tomoko, Imai Takashi, Kajiwara Chiaki, Mizukami Shusaku, Nakai Akira, Nakayama Toshinori, Udono Heiichiro

    JOURNAL OF IMMUNOLOGY   185 ( 5 )   2693 - 2700   2010.9

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    Extracellular HSP90 associated with Ag peptides have been demonstrated to efficiently cross-prime T cells, following internalization by dendritic cells (DCs). In addition, the nature of cell-associated Ags required for cross-priming is implicated as peptides and proteins chaperoned by heat shock protein (HSP). However, the role of endogenous HSP in DCs during cross-presentation remains elusive. In this paper, we show that endogenous HSP90 is essential for cross-presentation of both soluble and cell-associated Ags in DCs. Cross-presentation of soluble OVA and OVA-loaded transporter associated with Ag processing-1-deficient cells by bone marrow-derived DCs and DC-like cell line DC2.4 was profoundly blocked by HSP90 inhibitors, whereas presentation of endogenously expressed OVA was only partially suppressed. Assays using small interfering RNA and heat shock factor-1-deficient DCs (with defective expression of HSP90alpha) revealed the pivotal role of HSP90alpha in cross-presentation. The results suggest that in addition to HSP90 in Ag donor cells, endogenous HSP90 in DCs plays an essential role during Ag cross-presentation and, moreover, points to a link between heat shock factor-1-dependent induction of HSP90alpha within DC and cytotoxic T cell immunity.

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  • Targeted inhibition of IL-10-secreting CD25- Treg via p38 MAPK suppression in cancer immunotherapy. Reviewed International journal

    Kozo Ohkusu-Tsukada, Masahiro Toda, Heiichiro Udono, Yutaka Kawakami, Kimimasa Takahashi

    European journal of immunology   40 ( 4 )   1011 - 21   2010.4

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    Cancer-induced immunotolerance mediated by inducible Treg (iTreg) is a major obstacle to cancer immunotherapy. In a basic study of immunotolerance, injection of an endogenous superantigen, i.e. the minor lymphocyte stimulatory (Mls)-1(a), into specific TCR Vbeta8.1-Tg mice enabled generation of anergic CD25(-) iTreg, the immunosuppressive function of which was maintained by IL-10 production via p38-MAPK activation. Interestingly, although p38-chemical inhibitor (p38-inhibitor) is capable of breaking CD25(-) iTreg-induced immunotolerance, the p38-inhibitor had hardly any immunotolerance breaking effect when CD25(+) Treg were present, suggesting that depletion of CD25(+) Treg is necessary for p38-inhibitor to be effective. Peptide OVA(323-339) iv.-injection into its specific TCR-Tg (OT-II) mice also induced adaptive tolerance by iTreg. Peptide immunotherapy with p38-inhibitor after CD25(+) Treg-depletion was performed in an OVA-expressing lymphoma E.G7-bearing tolerant model established by adoptive transfer of OT-II CD25(-) iTreg, which resulted in suppression of tumor growth. Similarly, the antitumor immunity induced by peptide immunotherapy in colon carcinoma CT26-bearing mice, in which the number of IL-10-secreting iTreg is increased, was augmented by treatment with p38-inhibitor after CD25(+) Treg-depletion and resulted in inhibition of tumor progression. These results suggest that simultaneous inhibition of two distinct Treg-functions may be important to the success of cancer immunotherapy.

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  • Heat shock proteins in antigen trafficking--implications on antigen presentation to T cells. Invited Reviewed International journal

    Heiichiro Udono, Tomoko Ichiyanagi, Shusaku Mizukami, Takashi Imai

    International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group   25 ( 8 )   617 - 25   2009.12

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    Heat shock proteins (HSP) are molecular chaperones implicated in facilitation of protein folding and translocation between distinct compartments, and hence in preventing protein from aggregation. In terms of proteolysis, HSP act as a double-edged sword, stimulating proteasome-dependent proteolysis while preventing the degradation of the same proteins, even though in both cases association of unfolded proteins with HSP is the initial step. The proteasomal degradation products are utilised as ligands of major histocompatibility complex (MHC) class I molecules to be recognised by CD8(+) T cells, leading to activation of cytotoxic T cell immunity indispensable in fighting virus infections and cancers. In this context, HSP-mediated antigen traffic towards proteasomal degradation is coupled with acquired T cell immunity. In addition, exogenous antigens internalised by dendritic cells (DC) are also forwarded to the proteasome, possibly through the ER-associated degradation (ERAD) system, based on the fusion of the ER-membrane to the endosome containing the antigens. Thus, antigens within endosomes might be translocated to the cytosol, possibly through the Sec61 complex recruited from ER and degraded by the proteasome, rendering their peptides presentable by MHC class I molecules, a process known as cross-presentation. Since binding protein (Bip) facilitates degradation of most ER luminal soluble proteins in yeast, it is possible that endosomal HSP in DC, mimicking the action of Bip, facilitate the degradation of internalised soluble antigens. This may explain why the HSP-peptide/protein complex is extremely efficient in terms of cross-presentation ability. In this review, we discuss how HSP are linked to the ubiquitin-dependent proteasome system to generate peptides presentable by MHC molecules.

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  • Hsp90-mediated assembly of the 26 S proteasome is involved in major histocompatibility complex class I antigen processing. Reviewed International journal

    Yamano T, Mizukami S, Murata S, Chiba T, Tanaka K, Udono H

    The Journal of biological chemistry   283 ( 42 )   28060 - 28065   2008.10

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    Heat shock protein 90 (hsp90) and the proteasome activator PA28 stimulate major histocompatibility complex (MHC) class I antigen processing. It is unknown whether hsp90 influences the proteasome activity to produce T cell epitopes, although association of PA28 with the 20 S proteasome stimulates the enzyme activity. Here, we show that hsp90 is essential in assembly of the 26 S proteasome and as a result, is involved in epitope production. Addition of recombinant hsp90alpha to cell lysate enhanced chymotrypsin-like activity of the 26 S proteasome in an ATP-dependent manner as determined by an in-gel hydrolysis assay. We successfully pulled down histidine-tagged hsp90alpha- and PA28alpha-induced, newly assembled 26 S proteasomes from the cell extracts for in vitro epitope production assay, and we found these structures to be sensitive to geldanamycin, an hsp90 inhibitor. We found a cleaved epitope unique to the proteasome pulled down by both hsp90alpha and PA28alpha, whereas two different epitopes were identified in the hsp90alpha- and PA28alpha-pulldowns, respectively. Processing of these respective peptides in vivo was enhanced faithfully by the protein combinations used for the proteasome pulldowns. Inhibition of hsp90 in vivo by geldanamycin partly disrupted the 26 S proteasome structure, consistent with down-regulated MHC class I expression. Our results indicate that hsp90 facilitates MHC class I antigen processing through epitope production in a complex of the 26 S proteasome.

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  • Allele-selective effect of PA28 in MHC class I antigen processing Reviewed International journal

    Taketoshi Yamano, Hidetoshi Sugahara, Shusaku Mizukami, Shigeo Murata, Tomoki Chiba, Keiji Tanaka, Katsuyuki Yui, Heiichiro Udono

    Journal of Immunology   181 ( 3 )   1655 - 1664   2008.8

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    PA28 is an IFN-γ-inducible proteasome activator and its genetic ablation causes complete loss of processing of certain Ags, but not all of them. The reason why this occurs and how PA28 influences the formation of peptide repertoires for MHC class I molecules remains unknown. In this study, we show the allele-specific role of PA28 in Ag processing. Retrovirus-transduced overexpression of PA28α decreased expression of Kd (D d) while it increased Kb and Ld on the cell surface. By contrast, overexpression of PA28αΔC5, a mutant carrying a deletion of its five C-terminal residues and capable of attenuating the activity of endogenous PA28, produced the opposite effect on expression of those MHC class I molecules. Moreover, knockdown of both PA28α and β by small-interfering RNA profoundly augmented expression of Kd and Dd, but not of Ld, on the cell surface. Finally, we found that PA28-associated proteasome preferentially digested within epitopic sequences of Kd, although correct C-terminal flankings were removed, which in turn hampered production of Kd ligands. Our results indicate that whereas PA28 negatively influences processing of Kd (Dd) ligands, thereby, down-regulating Ag presentation by those MHC class I molecules, it also efficiently produces Kb (Ld) epitopes, leading to up-regulation of the MHC molecules. Copyright © 2008 by The American Association of Immunologists, Inc.

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  • Both CD4+ and CD8+ T cell epitopes fused to heat shock cognate protein 70 (hsc70) can function to eradicate tumors. Reviewed International journal

    Mizukami S, Kajiwara C, Ishikawa H, Katayama I, Yui K, Udono H

    Cancer science   99 ( 5 )   1008 - 1015   2008.5

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    Vaccination with heat shock proteins (HSP) protects mice from challenge with the tumor from which the HSP were isolated. The antigenicity of HSP vaccination is thought to result from HSP-associated endogenous major histocompatibility complex class I peptides or their precursors. The vaccination effect can be achieved in an adjuvant-free manner and is mediated by CD8(+) T cells, indicating that HSP can act as a natural adjuvant and cross-prime T cells in vivo. We previously devised a recombinant vaccine composed of a CD8(+) T cell epitope fused to the carboxyl-terminus of hsc70 and demonstrated efficient generation of antigen-specific cytotoxic T lymphocyte (CTL) after vaccination with a few micrograms of the hsc70-CTL epitope fusion protein. The present study aimed to determine if the fusion protein vaccine could control tumor growth in vivo and whether simultaneous fusion of a CD4(+) T cell epitope to the amino terminus of the hsc70-CTL epitope would be a more potent vaccine compared to the CTL epitope alone. Ovalbumin (OVA)-derived 8 mer peptide, OVA(257-264), and 16mer peptide, OVA(265-280), were used as CD8(+) and CD4(+) T cell epitopes, respectively. Vaccination with hsc70-OVA(257-264) generated peptide specific CTL more effectively than a peptide plus incomplete Freund's adjuvant combination, and suppressed growth of OVA expressing EL4 (E.G7) and B16 melanoma tumor cells. Addition of OVA(265-280) to the amino-terminus of hsc70-OVA(257-264) (OVA(265-280)-hsc70-OVA(257-264)) enhanced the generation of the OVA(257-264)-specific CTL population, leading to better eradication of MO5 lung metastasis compared to hsc70-OVA(257-264). Our results suggest that fusion of both CD4(+) and CD8(+) T cell epitopes to hsc70 enhances tumor immunity beyond the effect of the CD8(+) T cell epitope alone.

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  • Cross-presentation of NY-ESO-1 cytotoxic T lymphocyte epitope fused to human heat shock cognate protein 70 by dendritic cells. Reviewed

    Susumu S, Nagata Y, Ito S, Matsuo M, Valmori D, Yui K, Udono H, Kanematsu T

    Nagasaki University   99 ( 1 )   107 - 112   2008.1

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  • Interferon regulatory factor 4 negatively regulates the production of proinflammatory cytokines by macrophages in response to LPS. Reviewed International journal

    Honma K, Udono H, Kohno T, Yamamoto K, Ogawa A, Takemori T, Kumatori A, Suzuki S, Matsuyama T, Yui K

    Proceedings of the National Academy of Sciences of the United States of America   102 ( 44 )   16001 - 16006   2005.11

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    A member of the IFN regulatory factor (IRF) family of transcription factors, IRF-4 is expressed in lymphocytes and macrophage/dendritic cells. Studies using IRF-4-deficient mice have revealed the critical roles of IRF-4 in lymphocyte responses. However, the role of IRF-4 in innate immune responses is not clearly understood. Here, we demonstrate that IRF-4 negatively regulates the production of proinflammatory cytokines by macrophages in response to Toll-like receptor (TLR) stimulation. Mice lacking IRF-4 are sensitive to LPS-induced shock, and their macrophages produce high levels of proinflammatory cytokines, including TNF-alpha and IL-6, in response to TLR ligands. The inhibitory role of IRF-4 in response to TLR stimulation was confirmed by the down-regulation of IRF-4 expression in normal macrophages by using the small interfering RNA technique and by the overexpression of IRF-4 in macrophage line RAW264.7. Activation of the important signaling pathways for cytokine production, NF-kappaB and JNK (c-Jun N-terminal kinase), was enhanced after LPS stimulation in IRF-4(-/-) macrophages. These results imply that IRF-4 negatively regulates TLR signaling and is inhibitory to the production of proinflammatory cytokines in response to TLR stimulation.

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  • Erratum: Regulation of the maintenance of peripheral T-cell anergy by TAB1-mediated p38α activation (Molecular and Cellular Biology (2004) 24, 16 (6957-6966)) Reviewed

    Kozo Ohkusu-Tsukada, Norio Tominaga, Heiichiro Udono, Katsuyuki Yui

    Molecular and Cellular Biology   25   8763   2005.10

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    DOI: 10.1128/MCB.25.19.8763.2005

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  • Regulation of the maintenance of peripheral T-cell anergy by TAB1-mediated p38α activation Reviewed

    Kozo Ohkusu-Tsukada, Norio Tominaga, Heiichiro Udono, Katsuyuki Yui

    Molecular and Cellular Biology   24 ( 16 )   6957 - 6966   2004.8

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    In anergic T cells, T-cell receptor (TCR)-mediated responses are functionally inactivated by negative regulatory signals whose mechanisms are poorly understood. Here, we show that CD4+ T cells anergized in vivo by superantigen Mls-1a express a scaffolding protein, transforming growth factor β-activated protein kinase 1-binding protein 1 (TAB1), that negatively regulates TCR signaling through the activation of mitogen-activated protein kinase p38α. TAB1 was not expressed in naive and activated CD4+ T cells. Inhibition of p38 activity in anergic T cells by a chemical inhibitor resulted in the recovery of interleukin 2 (IL-2) and the inhibition of IL-10 secretion. T-cell hybridoma 2B4 cells transduced with TAB1-containing retrovirus (TAB1-2B4 cells) showed activated p38α, inhibited extracellular signal-regulated kinase (ERK) activity, culminating in reduced IL-2 levels and increased IL-10 production. The use of a p38 inhibitor or cotransfection of a dominant-negative form of p38 in TAB1-2B4 cells resulted in the recovery of ERK activity and IL-2 production. These results imply that TAB1-mediated activation of p38α in anergic T cells regulates the maintenance of T-cell unresponsiveness both by inhibiting IL-2 production and by promoting IL-10 production.

    DOI: 10.1128/MCB.24.16.6957-6966.2004

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  • A pitfall in diagnosis of human prion diseases using detection of protease-resistant prion protein in urine: Contamination with bacterial outer membrane proteins Reviewed

    Hisako Furukawa, Katsumi Doh-Ura, Ryo Okuwaki, Susumu Shirabe, Kazuo Yamamoto, Heiichiro Udono, Takashi Ito, Shigeru Katamine, Masami Niwa

    Journal of Biological Chemistry   279 ( 22 )   23661 - 23667   2004.5

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    Because a definite diagnosis of prion diseases relies on the detection of the abnormal isoform of prion protein (PrPSc), it has been urgently necessary to establish a non-invasive diagnostic test to detect PrP Sc in human prion diseases. To evaluate diagnostic usefulness and reliability of the detection of protease-resistant prion protein in urine, we extensively analyzed proteinase K (PK)-resistant proteins in patients affected with prion diseases and control subjects by Western blot, a coupled liquid chromatography and mass spectrometry analysis, and N-terminal sequence analysis. The PK-resistant signal migrating around 32 kDa previously reported by Shaked et al. (Shaked, G. M., Shaked, Y., Kariv-Inbal, Z., Halimi, M., Avraham, I., and Gabizon, R. (2001) J. Biol. Chem. 276, 31479-31482) was not observed in this study. Instead, discrete protein bands with an apparent molecular mass of ∼37 kDa were detected in the urine of many patients affected with prion diseases and two diseased controls. Although these proteins also gave strong signals in the Western blot using a variety of anti-PrP antibodies as a primary antibody, we found that the signals were still detectable by incubation of secondary antibodies alone, i.e. in the absence of the primary anti-PrP antibodies. Mass spectrometry and N-terminal protein sequencing analysis revealed that the majority of the PK-resistant 37-kDa proteins in the urine of patients were outer membrane proteins (OMPs) of the Enterobacterial species. OMPs isolated from these bacteria were resistant to PK and the PK-resistant OMPs from the Enterobacterial species migrated around 37 kDa on SDS-PAGE. Furthermore, nonspecific binding of OMPs to antibodies could be mistaken for PrPSc. These findings caution that bacterial contamination can affect the immunological detection of prion protein. Therefore, the presence of Enterobacterial species should be excluded in the immunological tests for PrPSc in clinical samples, in particular, urine.

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  • Hsp-antigen fusion and their use for immunization Reviewed

    H Udono, T Saito, M Ogawa, Y Yui

    METHODS   32 ( 1 )   21 - 24   2004.1

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    Immunization with antigenic peptide non-covalently associated with HSP elicits the peptide specific CD8(+)T cell response. The evidence encourages us to test the vaccination effect of recombinant HSP to which antigenic peptides are genetically fused. In the fusion protein, there should be no empty HSP molecules that failed to associate with the peptide of interest, like in vitro reconstitution method, therefore, promising effect may be easily obtained. Recombinant proteins expressed in Escherichia coli often form inclusion bodies and are thereby obtained as insoluble proteins or as proteins lacking their original functions. We describe here a simple and rapid refolding method of histidine-tagged recombinant hsp70/hsp70-peptide complex using a Ni2+-agarose column chromatography, without taking a process of dialysis to remove denaturants. The hsp70(hsp70-peptide complex) expressed in E coli as a form of inclusion body was solubilized in 8 M urea containing buffer and applied to a Ni2+,agarose column. The bound hsp70 was refolded on the column by quick removal of urea with urea-free buffer and eluted with a denaturant-free and imidazole-containing buffer. The purified hsp70 was homogeneous and soluble. In addition, it had a very high ATPase activity and strong CTL inducing activity, whereas hsp70 prepared by conventional dialysis method had a negligible ATPase activity. This simple and rapid refolding method may provide a general method for a restoration of function (and/or immunization effect) and solubility of histidine-tagged recombinant HSP. (C) 2003 Elsevier Science (USA). All rights reserved.

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  • Development of T<inf>h</inf>1 and not T<inf>h</inf>2 immune responses in mice lacking IFN-regulatory factor-4 Reviewed

    Norio Tominaga, Kozo Ohkusu-Tsukada, Heiichiro Udono, Ryo Abe, Toshifumi Matsuyama, Katsuyuki Yui

    International Immunology   15 ( 1 )   1 - 10   2003.1

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    IFN-regulatory factor (IRF)-4 is a member of the IRF family of transcription factors expressed in lymphocytes and macrophages. The previous studies using mice deficient in the IRF-4 gene showed profound defects in function of both B and T cells. To further investigate the role of IRF-4 in CD4+ T cell function, IRF-4-/- mice were challenged with the intracellular pathogen Leishmania major. The mice were protected against L. major during the early phase of the infection and CD4+ T cells of the infected mice produced IFN-γ in response to L. major antigen. However, during the late phase of infection, lymphocyte numbers were dramatically reduced in the draining lymph nodes, resulting in the deterioration of the lesion, indicating that IRF-4 was required for sustained immune responses against L. major infection. The function of CD4+ T cells was further investigated using TCR transgenic mice lacking the IRF-4 gene. CD4+ T cells from IRF-4-/- mice produced IFN-γ and expressed T-bet after culture under Th1-skewing conditions in vitro. However, Th2 cell development was not observed after culture under Th2-polarizing conditions. Proliferation of CD4+ T cells to IL-4 was reduced in IRF-4-/- mice, suggesting the defects in the responsiveness to IL-4. Furthermore, stimulation of the IRF-4-/- CD4+ T cells with IL-4-induced activation of signal transducer and activator of transcription 6, but not expression of growth factor independent-1. Thus, development of CD4+ T cell subsets differentially depends on IRF-4; induction of Th1 response does not depend on IRF-4, while Th2 response depends entirely on IRF-4.

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  • Merozoite surface protein 1-specific immune response is protective against exoerythrocytic forms of Plasmodium yoelii Reviewed

    Y Kawabata, H Udono, K Honma, M Ueda, H Mukae, J Kadota, S Kohno, K Yui

    INFECTION AND IMMUNITY   70 ( 11 )   6075 - 6082   2002.11

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    One of the difficulties in developing an effective malaria vaccine is the antigenic change of the parasite during the life cycle. It is desirable that vaccine-induced protective immunity be effective at different stages of parasite development. Merozoite surface protein 1 (MSP1) is a candidate vaccine antigen against blood-stage malaria, but it is also expressed in the exoerythrocytic forms. It was not known, however, whether the anti-MSP1 immune response is effective against the liver-stage malaria parasite. We generated a recombinant protein of MSP1 fused to heat-shock cognate protein 70 (hsc70) and studied its vaccination effect. When C57BL/6 mice were immunized with the fusion protein prior to challenge infection with Plasmodium yoelii sporozoites, the onset of parasitemia was delayed or no parasitemia was observed. To determine whether this was due to the protective immunity against liver-stage parasites, P. yoelii-specific rRNA in the infected liver was quantitated by real-time reverse transcription-PCR analysis. The level of parasite-specific rRNA was reduced in mice immunized with the fusion protein of MSP1 and hsc70 but not with hsc70 alone, indicating that MSP1-specific immunity can be protective against the exoerythrocytic form of the parasite. Furthermore, the adoptive transfer experiments of immune lymphocytes and serum into naive mice suggested that the protective immunity was dependent on cellular and not Immoral immunity. Finally, the vaccine-induced protection was also observed in A/J, C3H, and BALB/c mice, suggesting that MSP1-specific protective immunity at the exoerythrocytic stage can be induced in animals over a wide range of genetic backgrounds.

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  • Two distinct pathways mediated by PA28 and hsp90 in major histocompatibility complex class I antigen processing Reviewed

    T Yamano, S Murata, N Shimbara, N Tanaka, T Chiba, K Tanaka, K Yui, H Udono

    JOURNAL OF EXPERIMENTAL MEDICINE   196 ( 2 )   185 - 196   2002.7

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    Major histocompatibility complex (MHC) class I ligands are mainly produced by the proteasome. Herein, we show that the processing of antigens is regulated by two distinct pathways. one requiring PA28 and the other hsp90. Both hsp90 and PA28 enhanced the antigen processing of ovalbumin (OVA). Geldanamycin, an inhibitor of hsp90, almost completely suppressed OVA antigen presentation in PA28alpha(-/-)/beta(-/-) lipopolysaccharide blasts, but not in wild-type cells, indicating that hsp90 compensates for the loss of PA28 and is essential in the PA28-independent pathway. In contrast, treatment of cells with interferon (IFN)-gamma, which induces PA28 expression, abrogated the requirement of hsp90, suggesting that IFN-gamma enhances the PA28-dependent path Nay, whereas it diminishes hsp90-dependent pathway. Importantly, IFN-gamma did not induce MHC class I expressions in PA28-deficient cells, indicating a prominent role for PA28 in IFN-gamma-stiniulated peptide supply. Thus, these two pathways operate either redundantly or specifically, depending on antigen species and cell type.

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  • Immunoproteasome assembly and antigen presentation in mice lacking both PA28alpha and PA28beta Reviewed

    Shigeo Murata, Heiichiro Udono, Nobuyuki Tanahashi, Nobuyuki Hamada, Ken Watanabe, Kei Adachi, Taketoshi Yamano, Katsuyuki Yui, Nobuyuki Kobayashi, Masanori Kasahara, Keiji Tanaka, Tomoki Chiba

    The EMBO Journal   20 ( 21 )   5898 - 5907   2001.11

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  • Generation of cytotoxic T lymphocytes by MHC class I ligands fused to heat shock cognate protein 70 Reviewed

    H Udono, T Yamano, Y Kawabata, M Ueda, K Yui

    INTERNATIONAL IMMUNOLOGY   13 ( 10 )   1233 - 1242   2001.10

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    Immunization with gp96 and heat shock cognate protein 70 (hsc70) purified with in vivo bound naturally occurring peptides or bound to synthetic peptides by in vitro reconstitution has been shown to induce peptide-specific cytotoxic T lymphocytes (CTL). In addition, mycobacterial heat shock protein 70 covalently fused to ovalbumin (OVA)-derived fragments has been shown to generate MHC class I-restricted CTL responses. Here, we genetically fused five different CTL epitopes, including peptides derived from Plasmodium yoelli circumsporozoite protein, tumor antigens, HY antigen and OVA, to either the N- or C-terminus of murine hsc70 and expressed the resulting proteins in Escherichia coli. Vaccination with all five fusion proteins induced peptide-specific CTL, indicating that no cognate flanking regions of CTL epitopes are necessary for the immune response. The point of injection was crucial for CTL induction. CD4(+) T cells were not required for the priming of CD8(+) T cells and vaccination with bone marrow-derived dendritic cells pulsed with hsc70 fusion proteins also elicited CTL responses. Furthermore, by using deletion mutants of hsc70, we identified amino acid residues 280-385 of hsc70 as the region most critical for inducing the CTL response.

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  • Identification of a tumor-associated contact-dependent activity which reversibly downregulates cytolytic function of CD8+ T cells Reviewed

    Daniel L. Levey, Heiichiro Udono, Michael Heike, Pramod K. Srivastava

    Cancer Immunity   1   1 - 14   2001.3

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    Tumors elicit an immune response in hosts and yet, paradoxically, often grow progressively with fatal consequences. This phenomenon has been attributed to the possible expression by tumor cells of immunomodulatory factors that overcome the anti-tumor effector functions of both specific and non-specific immune cells. This study reports on the ability of the methylcholanthrene- induced fibrosarcoma, Meth A, as well as other tumors of varied histological origins to downregulate the lytic activity of CD8+ T cells. The suppressive activity is contact-dependent and reversible. As tumor-bearing hosts are rarely immunosuppressed systemically, these findings may explain how local events within the tumor bed subvert the specific anti-tumor immune response.

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  • Prolonged survival of rat cardiac allograft with proinflammatory cytokine inhibitor Reviewed

    Isao Sano, Takao Takahashi, Takehiko Koji, Heiiciro Udono, Katuyuki Yui, Hiroyoshi Ayabe

    Journal of Heart and Lung Transplantation   20 ( 5 )   583 - 589   2001

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    Background: Proinflammatory cytokines, such as tumor necrosis factor (TNF-α) and interleukin-1 (IL-1), play important roles in acute allograft rejection. FR167653 is an inhibitor of these cytokines that acts through inhibition of the mitogen-activated protein kinase p38 pathway. We examined the effect of FR167653 on allograft rejection. Methods: We used Brown-Norway and Lewis rats as donors and recipients, respectively. We performed heterotopic cardiac transplantation. The control group consisted of untreated rats. In the experimental groups, recipients were intraperitoneally injected with FR167653 just after operation, followed by daily injection of the drug from Day 1 to 10. We divided 20 rats into 5 groups, which received varying doses of FR167653, ranging from 75 to 300 mg/kg/day. Results: In the control group, the mean graft survival was 6.8 ± 0.3 days. FR167653 at 150 mg/kg/day significantly prolonged the survival period (up to 12.1 ± 1.5 days, p = 0.002). Histologically, FR167653 markedly suppressed cellular infiltration on Day 5 post-transplantation. The serum level of TNF-α in the control group was persistently elevated from 9.3 ± 3.9 pg/ml to 11.3 ± 3.8 pg/ml, whereas FR167653 significantly suppressed the level to &lt
    1.4 ± 1.4 pg/ml.ConclusionsFR167653 prolonged rat cardiac allograft survival by suppressing the action of proinflammatory cytokines. Copyright © 2001 International Society for Heart and Lung Transplantation.

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  • Heat shock protein 70 (hsp70) as a major target of the antibody response in patients with pulmonary cryptococcosis Reviewed

    H Kakeya, H Udono, S Maesaki, E Sasaki, S Kawamura, MA Hossain, Y Yamamoto, T Sawai, M Fukuda, K Mitsutake, Y Miyazaki, K Tomono, T Tashiro, E Nakayama, S Kohno

    CLINICAL AND EXPERIMENTAL IMMUNOLOGY   115 ( 3 )   485 - 490   1999.3

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    Cryptococcus neoformans causes infection in individuals with defective T cell function, such as AIDS, as well as without underlying disease. It has been suggested that humoral as well as cellular immunity might play an important role in the immune response to C. neoformans infection. We have recently shown, using immunoblotting, that the 70-kD hsp family of C. neoformans was the major target molecule of the humoral response in murine pulmonary cryptococcosis. In this study we also used immunoblotting to define the antibody responses in the sera of 24 patients with pulmonary cryptococcosis: 21 proven and three suspected diagnoses. Anti-C. neoformans hsp70 antibody was detected in 16 of 24 (66.7%) patients with pulmonary cryptococcosis. Fourteen of 17 (82.3%) patients with high antigen titres (greater than or equal to 1:8) and two of seven (28.6%) patients with low titres (less than or equal to 1:4) had detectable levels of anti-hsp70 antibody. Sera from patients positive for anti-hsp70 antibody showed high titres in the Eiken latex agglutination test for the detection of serum cryptococcal antigen. Our results indicate that the 70-kD hsp family from C. neoformans appears to be a major target molecule of the humoral response, not only in murine pulmonary cryptococcosis, but also in human patients with pulmonary cryptococcosis.

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  • Isolation of MHC Class I-Restricted Tumor Antigen Peptide and Its Precursors Associated with Heat Shock Proteins hsp70, hsp90, and gp96 Reviewed

    T Ishii, H Udono, T Yamano, H Ohta, A Uenaka, T Ono, A Hizuta, N Tanaka, PK Srivastava, E Nakayama

    JOURNAL OF IMMUNOLOGY   162 ( 3 )   1303 - 1309   1999.2

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    We have previously demonstrated that vaccination with heat shock proteins hsp70, hsp90, and gp96 elicits specific immunity against the tumor from which the hsps were purified. Although the association of tumor Ag peptides with these hsps have been suggested, the identification of the peptides or their precursors stripped from the hsps remained to be resolved. We show in this report that an L-d-restricted cytotoxic T lymphocyte epitope of a mouse leukemia RL male 1 and its precursors are associated with the chaperones hsp90 and hsp70 in the cytosol and gp96 in the lumen of the endoplasmic reticulum, Hsp70 was associated,vith only final sized octamer, while hsp90 was found to associate with the octamer and two distinct precursor peptides, The gp96,vas associated with the octamer and one of the two precursors. Thus, each of the hsps bound a distinct set of peptides, Our results have demonstrated for the first time that the hsps associate not only with final sized tumor Ag peptide but also with its precursors. The implication of this evidence is also discussed in terms of the roles of hsps in MHC class I Ag processing/presentation.

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  • Variable expression on lung cancer cell lines of HLA-A2-binding MAGE-3 peptide recognized by cytotoxic T lymphocytes Reviewed

    T Takaki, A Hiraki, A Uenaka, S Gomi, K Itoh, H Udono, A Shibuya, T Tsuji, S Sekiguchi, E Nakayama

    INTERNATIONAL JOURNAL OF ONCOLOGY   12 ( 5 )   1103 - 1109   1998.5

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    Cytotoxic T lymphocytes (CTL) specific for HLA-A2-binding MAGE-3 peptide (FLWGPRALV) were generated by repetitive stimulation of PBMC with the peptide in the presence of EBV-transformed B blasts and IL-2. Using these CTL, we investigated the expression of the HLA-A2-binding MAGE-3 peptide on lung cancer cell lines. Of 14 cell lines investigated, 1-87, PC-9, OU-LC-KI, 11-18 and LK87 were derived from HLA-A2 positive patients. But cytofluorometry analysis showed that 1-87, PC-9 and OU-LC-KI, but not 11-18 or LK87 expressed the HLA-A2 antigen. All five cell lines expressed MAGE-3 gene mRNA. Twelve of thirteen CTL lines from two HLA-A2 positive donors showed no cytotoxicity against any of the 14 lung cancer cell lines. CTL line TI-1 showed cytotoxicity against 1-87 but not against any of the other cell lines. Treatment of 1-87 with IFN-gamma greatly augmented the cytotoxicity of TI-1 and induced it in the other 12 CTL lines, confirming the expression of the peptide on 1-87. No cytotoxicity was induced by IFN- gamma treatment of PC-9 or OU-LC-KI. However, PC-9 and OU-LC-KI pulsed with the peptide were killed efficiently by all of the CTL lines, suggesting no expression of the peptide on those cells. A low level of cytotoxicity was induced on 11-18 but not LK87 by IFN-gamma treatment, although expression of the HLA-A2 antigen was not observed by cytofluorometry. These findings showed that expression of the HLA-A2-binding MAGE-3 peptide recognized by CTL was variable on lung cancer cell lines.

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  • Heat Shock Protein–Peptide Complexes, Reconstituted In Vitro, Elicit Peptide-specific Cytotoxic T Lymphocyte Response and Tumor Immunity Reviewed

    Nathalie E. Blachere, Zihai Li, Rajiv Y. Chandawarkar, Ryuichiro Suto, Navdeep S. Jaikaria, Sreyashi Basu, Heiichiro Udono, Pramod K. Srivastava

    Journal of Experimental Medicine   186 ( 8 )   1315 - 1322   1997.10

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    Heat shock protein (HSP) preparations derived from cancer cells and virus-infected cells have been shown previously to elicit cancer-specific or virus-specific immunity. The immunogenicity of HSP preparations has been attributed to peptides associated with the HSPs. The studies reported here demonstrate that immunogenic HSP–peptide complexes can also be reconstituted in vitro. The studies show that (a) complexes of hsp70 or gp96 HSP molecules with a variety of synthetic peptides can be generated in vitro; (b) the binding of HSPs with peptides is specific in that a number of other proteins tested do not bind synthetic peptides under the conditions in which gp96 molecules do; (c) HSP–peptide complexes reconstituted in vitro are immunologically active, as tested by their ability to elicit antitumor immunity and specific CD8+ cytolytic T lymphocyte response; and (d) synthetic peptides reconstituted in vitro with gp96 are capable of being taken up and re-presented by macrophage in the same manner as gp96– peptides complexes generated in vivo. These observations demonstrate that HSPs are CD8+ T cell response–eliciting adjuvants.

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  • Comparison of tumor-specific immunogenicities of stress-induced proteins gp96, hsp90, and hsp70. Reviewed

    H Udono, P K Srivastava

    1994.6

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  • Cellular requirements for tumor-specific immunity elicited by heat shock proteins: tumor rejection antigen gp96 primes CD8+ T cells in vivo. Reviewed

    H. Udono, D. L. Levey, P. K. Srivastava

    Proceedings of the National Academy of Sciences   91 ( 8 )   3077 - 3081   1994.4

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  • Heat shock proteins transfer peptides during antigen processing and CTL priming Reviewed

    Srivastava PK1, Udono H, Blachere NE, Li Z

    1994.1

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  • Heat shock protein 70-associated peptides elicit specific cancer immunity. Reviewed

    H Udono, P K Srivastava

    Journal of Experimental Medicine   178 ( 4 )   1391 - 1396   1993.10

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    Vaccination of mice with heat shock protein 70 (hsp70) preparations derived from the Meth A sarcoma, but not from normal tissues, renders the mice immune to a substantial challenge with Meth A sarcoma. The immunogenicity is dose dependent and tumor specific. Treatment of an antigenically active hsp70 preparation with ATP followed by removal of low-molecular weight material leaves hsp70 intact, as judged by SDS-PAGE but results in loss of antigenicity, as judged by tumor rejection assays. Separation of this low-molecular weight material on a C18 reverse-phase column shows a diverse array of peptides with molecular mass between 1,000 and 5,000 daltons. Our data indicate that antigenicity of hsp70 preparations derives, not from hsp70 per se, but from associated peptides. These observations may suggest a novel method of using the peptide-binding property of hsp70 for specific vaccination against cancer and infectious diseases.

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  • PARTICIPATION OF A DOMINANT CYTOTOXIC T-CELL POPULATION DEFINED BY A MONOCLONAL-ANTIBODY IN SYNGENEIC ANTITUMOR RESPONSES Reviewed

    Y MATSUBAYASHI, T HIRAMA, A MORIOKA, M IWASHIRO, T MASUDA, H UCHINO, S TAKESHITA, H YAMAGISHI, H UDONO, M MIENO, E NAKAYAMA, H SHIKU, A UENAKA, K KURIBAYASHI

    EUROPEAN JOURNAL OF IMMUNOLOGY   20 ( 9 )   2095 - 2103   1990.9

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  • ROLES OF CD4+ AND CD8+ CELLS, AND THE EFFECT OF ADMINISTRATION OF RECOMBINANT MURINE INTERFERON-GAMMA IN LISTERIAL INFECTION Reviewed

    T SASAKI, M MIENO, H UDONO, K YAMAGUCHI, T USUI, K HARA, H SHIKU, E NAKAYAMA

    JOURNAL OF EXPERIMENTAL MEDICINE   171 ( 4 )   1141 - 1154   1990.4

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  • BLOCKING OF CYTO-TOXIC T-CELL FUNCTION OF MOLF/EI MICE BY ANTI-LY 35.1 MONOCLONAL-ANTIBODY Reviewed

    M MIENO, H UDONO, S IKEGAMI, N TADA, H SHIKU, E NAKAYAMA

    IMMUNOLOGY   68 ( 3 )   431 - 433   1989.11

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  • THE ROLES OF CD8+ AND CD4+ CELLS IN TUMOR REJECTION Reviewed

    H UDONO, M MIENO, H SHIKU, E NAKAYAMA

    JAPANESE JOURNAL OF CANCER RESEARCH   80 ( 7 )   649 - 654   1989.7

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  • PROLIFERATIVE RESPONSE OF CLONED CTL LINE 10B-5 UPON STIMULATION WITH SOLUBLE CLONOTYPIC MONOCLONAL-ANTIBODY AND ITS BLOCKING BY ANTI-LYT-2 ANTIBODY

    H UDONO, K KURIBAYASHI, T FUJITA, M MIENO, H SHIKU, E NAKAYAMA

    IMMUNOBIOLOGY   178 ( 4-5 )   390 - 400   1989.2

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    DOI: 10.1016/s0171-2985(89)80061-0

    Web of Science

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  • ANTI-IDIOTYPIC ANTIBODIES AGAINST UV-INDUCED TUMOR-SPECIFIC CTL CLONES - PREPARATION IN SYNGENEIC COMBINATION Reviewed

    K KURIBAYASHI, C TANAKA, Y MATSUBAYASHI, T MASUDA, H UDONO, M ABE, E NAKAYAMA, H SHIKU

    JOURNAL OF IMMUNOLOGY   141 ( 11 )   4074 - 4080   1988.12

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MISC

  • Metabolic Intervention to Tumor microenvironment for Cancer Immunotherapy Invited

    鵜殿平一郎, 西田充香子, 工藤生

    リンパ学   44 ( Supplement )   2021

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  • メトホルミンと抗PD-1抗体併用によるCD8T細胞依存性の腫瘍血管正常化

    工藤 生, Zhang Xingda, 西田 充香子, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   25回   117 - 117   2021.5

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  • 『がん免疫療法実用化の時代』〜あなたが抱く基礎・臨床の課題を皆で考える2021〜 がん免疫療法実用化の時代 腫瘍微小環境の"3低"を標的にできるか?

    鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   25回   48 - 48   2021.5

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  • 肺腺癌マウスのEP-4阻害剤と抗PD-1抗体の併用療法の解析

    徳増 美穂, 西田 充香子, 川口 高正, 吉田 隆雄, 工藤 生, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   25回   114 - 114   2021.5

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  • Egfr改変肺癌マウスモデルを用いたEGFR-TKI、抗VEGFR-2抗体と抗PD-1抗体併用療法の検討

    西井 和也, 大橋 圭明, 中須賀 崇匡, 平生 敦子, 大川 祥, 渡邉 洋美, 狩野 裕久, 原 尚史, 安東 千裕, 二宮 貴一朗, 加藤 有加, 二宮 崇, 久保 寿夫, 頼 冠名, 市原 英基, 堀田 勝幸, 田端 雅弘, 鵜殿 平一郎, 前田 嘉信, 木浦 勝行

    肺癌   60 ( 6 )   531 - 531   2020.10

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  • メトホルミンによる糖代謝バランスの改善と腫瘍微小環境の変化に関する組織学的解析

    工藤 生, 西田 充香子, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   24回   99 - 99   2020.9

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  • ROS依存的なNrf2/mTORC1経路の活性化はメトホルミンと抗PD-1抗体の併用効果を誘導する

    西田 充香子, 山下 奈穂子, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   24回   150 - 150   2020.9

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  • 2型糖尿病に対するメトホルミンの抗腫瘍効果

    野島 一郎, 榮川 伸吾, 梶谷 展生, 勅使川原 早苗, 宮本 聡, 利根 淳仁, 内田 治仁, 中司 敦子, 江口 潤, 四方 賢一, 鵜殿 平一郎, 和田 淳

    糖尿病   63 ( Suppl.1 )   S - 111   2020.8

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  • 古くて新しい薬「メトホルミン」〜基礎研究から見えてきた多面的作用〜 メトホルミン誘導性ミトコンドリア活性酸素によるがん免疫再起動

    鵜殿 平一郎, 西田 充香子, 工藤 生

    糖尿病   63 ( Suppl.1 )   S - 47   2020.8

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  • Metabolic intervention facilitates anti-tumor immunity

    西田充香子, 鵜殿平一郎

    医学のあゆみ   275 ( 1 )   2020

  • Metabolic reprograming of tumor microenvironment improves efficacy of cancer immunotherapy via reactivation of exhausted T cells

    西田充香子, 鵜殿平一郎

    実験医学   38 ( 19 )   2020

  • 2型糖尿病に対するメトホルミンの抗腫瘍効果

    野島一郎, 榮川伸吾, 梶谷展生, 勅使川原早苗, 宮本聡, 利根淳仁, 内田治仁, 中司敦子, 江口潤, 四方賢一, 鵜殿平一郎, 和田淳

    糖尿病(Web)   63 ( Suppl )   2020

  • 腫瘍免疫と微小環境 遺伝子改変EGFR変異肺癌マウスモデルの腫瘍免疫回避経路の検討

    西井 和也, 大橋 圭明, 槇本 剛, 渡邉 洋美, 狩野 裕久, 原 尚史, 中須賀 崇匡, 安東 千裕, 二宮 貴一朗, 加藤 有加, 二宮 崇, 久保 寿夫, 頼 冠名, 市原 英基, 堀田 勝幸, 田端 雅弘, 鵜殿 平一郎, 木浦 勝行

    肺癌   59 ( 6 )   567 - 567   2019.11

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  • 肺腺がん細胞のCOX-2欠損はその固形腫瘍形成と増殖を抑制する(COX-2 deficiency in lung adenocarcinoma cells suppresses solid tumor formation and slow down the growth in vivo)

    徳増 美穂, 山崎 千尋, 西田 充香子, 鵜殿 平一郎

    日本癌学会総会記事   78回   P - 2275   2019.9

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  • MUSCAT-Assay法での自己抗体モニタリングによる腫瘍免疫応答評価

    二見 淳一郎, 本莊 知子, 吉岡 実咲, 勝河 祐希, Ahmadi Hannaneh, 尾崎 龍之介, 木下 理恵, 鵜殿 平一郎, 垣見 和宏

    日本がん免疫学会総会プログラム・抄録集   23回   141 - 141   2019.7

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  • がん、糖尿病の合併症 メトホルミンによる腫瘍微小環境の代謝改変と抗腫瘍免疫応答

    鵜殿 平一郎

    糖尿病合併症   33 ( 2 )   274 - 278   2019.7

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  • メトホルミンによる糖代謝バランスの改善と腫瘍微小環境の変化に関する組織学的解析

    工藤 生, 西田 充香子, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   23回   98 - 98   2019.7

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  • 代謝から読み解く腫瘍免疫研究

    鵜殿 平一郎

    日本医学会総会会誌   30回   柱1 - 2   2019.4

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  • レジオネラをめぐる新展開 レジオネラ感染における宿主免疫応答

    梶原 千晶, 鵜殿 平一郎, 石井 良和, 舘田 一博

    日本細菌学雑誌   74 ( 1 )   30 - 30   2019.3

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  • 癌と免疫の対峙を代謝で読み解く腫瘍免疫学 メトホルミンによる癌治療への異次元戦略

    鵜殿 平一郎

    中部大学生命健康科学研究所紀要   15   1 - 17   2019.3

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  • 【糖尿病とがん】メトホルミンと発がんリスク

    野島 一郎, 和田 淳, 鵜殿 平一郎

    医薬ジャーナル   55 ( 1 )   103 - 106   2019.1

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    <文献概要>糖尿病により,がん罹患リスクが上昇することはよく知られている。だが,現在のところ血糖コントロールを厳密にすることでがん罹患率が減少するといった良質なエビデンスは存在しない。しかし,メトホルミン内服によりがん罹患率,がん死亡率が低下することは,メタアナリシスから示唆されている。In vivo,in vitroの実験からメトホルミンの抗腫瘍効果のメカニズムは徐々に解明されつつあるが,近年免疫細胞を介して抗腫瘍効果を発現しているとの報告があり,注目を浴びている。メトホルミンはUKPDS(United Kingdom Prospective Diabetes Study)の報告以降「古くて新しい薬」と言われているが,現在でもさまざまな薬理作用が研究されていることから,今でも「古くて新しい薬」である。

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    Other Link: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00065&link_issn=&doc_id=20190116150015&doc_link_id=10.20837%2F1201901103&url=https%3A%2F%2Fdoi.org%2F10.20837%2F1201901103&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

  • バイオマーカー 4)【食道癌】CD8+T細胞,CD204+マクロファージを中心に

    宮本学, 宮本学, 鵜殿平一郎

    がん免疫療法   3 ( 2 )   2019

  • 腫瘍免疫応答の正負の調節機構 11.腫瘍微小環境の代謝改変による腫瘍免疫の向上-代謝で読み解く免疫細胞と腫瘍細胞の攻防

    西田充香子, 鵜殿平一郎

    実験医学   37 ( 15 )   2019

  • 免疫の基礎・トランスレーショナルリサーチ 腫瘍内CD8T細胞の代謝制御による免疫疲弊解除

    鵜殿 平一郎, 渡邉 元嗣, 西田 充香子

    肺癌   58 ( 6 )   437 - 437   2018.10

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  • がん、糖尿病の合併症 メトホルミンによる腫瘍微小環境の代謝改変と抗腫瘍免疫応答

    鵜殿 平一郎

    糖尿病合併症   32 ( Suppl.1 )   158 - 158   2018.10

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  • 食道癌術前化学療法患者における末梢血CD8 T細胞の多能性の解析(Multifunctionality of Peripheral Blood CD8 T Cells in Esophageal Cancer Patients with Preoperative Chemotherapy)

    宮本 学, 榮川 伸吾, 鵜殿 平一郎, 藤原 俊義

    日本癌学会総会記事   77回   1384 - 1384   2018.9

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  • 肥満モデルマウスに対するメトホルミンの抗腫瘍効果

    野島 一郎, 榮川 伸吾, 鵜殿 平一郎, 和田 淳

    肥満研究   24 ( Suppl. )   242 - 242   2018.9

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  • 腫瘍免疫の制御によるがん治療の展開 腫瘍微小環境の代謝改変は免疫を介して腫瘍増殖を抑制する(Regulation of tumor immunity and evolution of cancer treatments Metabolic reprogramming of tumor microenvironment leads to immune-mediated tumor growth inhibition)

    鵜殿 平一郎, 西田 充香子, 榮川 伸吾, 國定 勇希, 上原 健敬

    日本癌学会総会記事   77回   887 - 887   2018.9

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  • 糖代謝:疾患の発症と進展のスイートスポット 腫瘍微小環境の代謝改変によるがん免疫治療研究

    鵜殿 平一郎, 西田 充香子

    日本生化学会大会プログラム・講演要旨集   91回   [2S07a - 01]   2018.9

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  • ストレスが拓く腫瘍微小環境の代謝改変とがん免疫治療への応用

    鵜殿 平一郎

    Thermal Medicine   34 ( Suppl. )   70 - 70   2018.8

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  • 代謝とがん免疫 メトホルミンと抗PD-1抗体併用療法における相乗効果の分子メカニズム

    西田 充香子, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   22回   55 - 55   2018.7

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  • 難治性/再発性固形腫瘍に対するメトホルミンと併用したニボルマブ療法の第Ib相試験(Phase Ib trial of nivolumab combined with metformin for refractory/recurrent solid tumors)

    久保 寿夫, 堀田 勝幸, 二宮 崇, 加藤 博也, 堀口 繁, 高本 篤, 上月 稔幸, 野上 尚之, 石井 浩, 仁科 智裕, 原田 大二郎, 豊岡 伸一, 岡田 裕之, 藤原 俊義, 鵜殿 平一郎, 木浦 勝行

    日本がん免疫学会総会プログラム・抄録集   22回   141 - 141   2018.7

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  • 抗酸化ストレス応答はメトホルミンによる抗腫瘍効果を誘導する

    西田 充香子, 山下 奈穂子, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   22回   81 - 81   2018.7

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  • 悪性黒色腫に対する抗PD-1抗体による末梢血多機能性CD8陽性T細胞と臨床的有効性の解析

    眞部 恵子, 加持 達弥, 山崎 修, 岩月 啓氏, 榮川 伸吾, 木村 裕司, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   22回   137 - 137   2018.7

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  • メトホルミンは腫瘍内骨髄球系細胞の代謝を制御し骨肉腫増殖を抑制する

    上原 健敬, 榮川 伸吾, 吉田 晶, 長谷井 嬢, 中田 英二, 国定 俊之, 尾崎 敏文, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   22回   155 - 155   2018.7

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  • 腫瘍浸潤リンパ球(TIL)を含んだ腫瘍解離細胞(DTC)の保存

    渡邊 元嗣, 高橋 優太, 冨田 秀太, 宗 淳一, 松原 岳大, 難波 圭, 佐藤 博紀, 森田 瑞樹, 枝園 和彦, 山本 寛斉, 鵜殿 平一郎, 豊岡 伸一

    日本がん免疫学会総会プログラム・抄録集   22回   161 - 161   2018.7

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  • 腫瘍細胞におけるHsp90αおよびHsp90βアイソフォームの機能解析

    山崎 千尋, 趙 維洋, 西田 充香子, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   22回   66 - 66   2018.7

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  • 2型糖尿病治療薬メトホルミンのヒト末梢血CD8T細胞に対する影響の検討

    渡邉 元嗣, 榮川 伸吾, 豊岡 伸一, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   22回   74 - 74   2018.7

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  • メトホルミン研究から学んだこと

    鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   22回   35 - 35   2018.7

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  • 2型糖尿病末梢血CD8陽性T細胞における糖代謝異常と免疫疲弊

    野島 一郎, 榮川 伸吾, 樋口 千草, 勅使川原 早苗, 宮本 聡, 利根 淳仁, 中司 敦子, 江口 潤, 小川 大輔, 四方 賢一, 鵜殿 平一郎, 和田 淳

    糖尿病   61 ( 5 )   330 - 330   2018.5

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  • 代謝破綻と疾患 腫瘍微小環境の代謝改変とがん免疫治療への応用

    鵜殿 平一郎, 榮川 伸吾, 國定 勇希, 西田 充香子, 上原 健敬

    日本栄養・食糧学会大会講演要旨集   72回   174 - 174   2018.4

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  • 2型糖尿病末梢血CD8陽性T細胞における免疫疲弊とメトホルミンの効果

    野島 一郎, 榮川 伸吾, 樋口 千草, 勅使川原 早苗, 宮本 聡, 利根 淳仁, 中司 敦子, 江口 潤, 小川 大輔, 四方 賢一, 鵜殿 平一郎, 和田 淳

    糖尿病   61 ( Suppl.1 )   S - 211   2018.4

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  • 【がん免疫療法の新たな展開】代謝と抗腫瘍エフェクターT細胞

    木村 裕司, 榮川 伸吾, 鵜殿 平一郎

    最新医学   73 ( 2 )   224 - 229   2018.2

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    近年、T細胞のエフェクター機能について、細胞内代謝の視点からアプローチした研究報告が散見されている。特にT細胞受容体(TCR)シグナルの下流では、解糖系の亢進が種々の機序によってT細胞のエフェクター機能につながっていることが明らかになってきた。さらには、アミノ酸代謝やエネルギーセンサー分子であるAMPKの活性化がそれらに深くかかわっていることも報告されている。CD8陽性T細胞の代謝を調節し、そのエフェクター機能を高めることで抗腫瘍効果をもたらすがん免疫療法のさらなる進歩に期待したい。(著者抄録)

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  • 2型糖尿病末梢血CD8陽性T細胞における免疫疲弊とメトホルミンの効果

    野島一郎, 榮川伸吾, 樋口千草, 勅使川原早苗, 宮本聡, 利根淳仁, 中司敦子, 江口潤, 小川大輔, 四方賢一, 鵜殿平一郎, 和田淳

    糖尿病(Web)   61 ( Suppl )   2018

  • ホルミシスネオバイオロジー 腫瘍微小環境の代謝改変によるがん免疫リブート

    鵜殿 平一郎

    生命科学系学会合同年次大会   2017年度   [2AW23 - 1]   2017.12

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  • 【腫瘍免疫と癌免疫療法】メトホルミンによるCD8+TILの代謝改変におけるreactive oxygen species(ROS)の関与

    西田 充香子, 鵜殿 平一郎

    臨床免疫・アレルギー科   68 ( 6 )   583 - 588   2017.12

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  • 抗酸化ストレス応答はメトホルミンによる抗腫瘍効果を誘導する

    西田 充香子, 山下 菜穂子, 鵜殿 平一郎

    生命科学系学会合同年次大会   2017年度   [1P - 1021]   2017.12

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  • 【がん局所微小環境と免疫療法】がん微小環境における代謝競合

    榮川 伸吾, 鵜殿 平一郎

    癌と化学療法   44 ( 11 )   972 - 976   2017.11

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    代謝はT細胞応答に密接に関与しており、感染やがんなどの生体防御においても重要である。特に解糖系(糖代謝)はエフェクターT細胞機能に不可欠な代謝経路である。近年、がん微小環境下は低酸素/低栄養状態であり、このような環境下ではエフェクターT細胞は本来の機能が発揮し難いことが明らかにされている。このような環境におけるT細胞の機能を制御するために、様々な代謝薬を用いたがん免疫療法に関する研究が展開されつつある。本稿では、がん微小環境における"代謝競合"とそれに伴う腫瘍浸潤T細胞の機能低下について言及する。(著者抄録)

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  • 2型糖尿病薬メトホルミンによる腫瘍内制御性T細胞の機能抑制

    國定 勇希, 榮川 伸吾, 友信 奈保子, 銅前 昇平, 上原 健敬, 堀 昌平, 古澤 之裕, 長谷 耕二, 佐々木 朗, 鵜殿 平一郎

    日本癌学会総会記事   76回   J - 1090   2017.9

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  • がん免疫療法の一段の進化へむけて 腫瘍浸潤免疫細胞の代謝は抗腫瘍免疫応答を制御する

    鵜殿 平一郎, 榮川 伸吾, 國定 勇希, 上原 健敬, 渡邉 元嗣, 木村 裕司, 佐々木 朗, 尾崎 敏文, 豊岡 伸一, 藤原 俊義

    日本癌学会総会記事   76回   S10 - 5   2017.9

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  • 癌性腹膜炎における抗腫瘍免疫応答を介したメトホルミンの効果

    平山 昂仙, 永田 康浩, 西田 充香子, 小林 慎一郎, 米田 晃, 金高 賢悟, 松尾 光敏, 鵜殿 平一郎, 江口 晋

    日本癌学会総会記事   76回   P - 1217   2017.9

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  • 胃癌患者における末梢血中CD8T細胞の多機能性と代謝の解析

    木村 裕司, 榮川 伸吾, 鵜殿 平一郎, 藤原 俊義

    日本癌学会総会記事   76回   P - 1243   2017.9

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  • メトホルミンはアミノ酸代謝を介してCD8T細胞の好気的解糖を促進する

    榮川 伸吾, 友信 奈保子, 山下 菜穂子, 野島 一郎, 木村 裕司, 宮本 学, 福田 真嗣, 長谷 耕二, 鵜殿 平一郎

    日本癌学会総会記事   76回   J - 1032   2017.9

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  • 胃癌患者末梢血中CD8T細胞の多機能性と代謝の解析

    木村 裕司, 榮川 伸吾, 藤原 俊義, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   21回   97 - 97   2017.6

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  • 胃癌患者末梢血中CD8T細胞の多機能性と代謝の解析

    木村 裕司, 榮川 伸吾, 野島 一郎, 藤原 俊義, 鵜殿 平一郎

    Cytometry Research   27 ( Suppl. )   53 - 53   2017.6

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  • 2型糖尿病患者CD8陽性T細胞におけるメトホルミンの影響

    野島 一郎, 榮川 伸吾, 友信 奈保子, 木村 裕司, 渡邉 元嗣, 鵜殿 平一郎

    Cytometry Research   27 ( Suppl. )   55 - 55   2017.6

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  • CTLs revisited 疾患発症・病態制御におけるCTLについての再考察 がん微小環境におけるT細胞の代謝疲弊

    榮川 伸吾, 鵜殿 平一郎

    Cytometry Research   27 ( Suppl. )   39 - 39   2017.6

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  • 【がん代謝 ワールブルグを超えて全容解明に挑む トリガーとなる分子、腸内細菌や免疫細胞の関与、標的治療の展望】(第3章)がんの代謝を制御する因子 免疫細胞の代謝とがん

    鵜殿 平一郎

    実験医学   35 ( 10 )   1672 - 1677   2017.6

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    T細胞は、その分化・成熟および抗原刺激に続くclonal expansion、さらには記憶T細胞への移行において、刻々と代謝システムを変化させている。これは、T細胞抗原受容体シグナルにはしまる各種転写因子の活性化と制御による。一方、薬剤等で強制的に代謝を改変した場合、逆にT細分の分化・増殖と機能を変化させうることが徐々に明らかになってきた。すなわち、代謝改変は免疫細胞のあり方を変化させることのできる新たな免疫調節法を提示する。とりわけ、がんに対する免疫応答を改善できる可能性がある。(著者抄録)

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  • 悪性黒色腫に対する免疫チェックポイント阻害薬による多機能性T細胞解析

    山崎 修, 眞部 恵子, 加持 達弥, 梅村 啓史, 岩月 啓氏, 榮川 伸吾, 木村 裕司, 鵜殿 平一郎

    日本皮膚悪性腫瘍学会学術大会プログラム・抄録集   33回   142 - 142   2017.5

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  • 2型糖尿病におけるメトホルミンの免疫機能への影響

    野島 一郎, 榮川 伸吾, 宮本 聡, 勅使川原 早苗, 利根 淳仁, 中司 敦子, 江口 潤, 四方 賢一, 鵜殿 平一郎, 和田 淳

    糖尿病   60 ( Suppl.1 )   S - 259   2017.4

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  • がん免疫療法の今後

    上田 龍三, 鵜殿 平一郎, 河上 裕, 鳥越 俊彦, 西川 博嘉

    がん免疫療法   1 ( 1 )   10 - 18   2017.4

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  • 2型糖尿病治療薬メトホルミンのレジオネラ感染に及ぼす影響

    梶原 千晶, 鵜殿 平一郎, 石井 良和, 舘田 一博

    日本細菌学雑誌   72 ( 1 )   150 - 150   2017.2

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  • 【がん免疫療法-がん完治に向けての新たな治療法の探索-】メトホルミンによる代謝改変と抗腫瘍免疫応答

    友信 奈保子, 榮川 伸吾, 鵜殿 平一郎

    日本臨床   75 ( 2 )   323 - 328   2017.2

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  • 腫瘍微小環境における代謝とがんに対する免疫監視 がんの免疫監視機構

    鵜殿平一郎

    がん免疫療法   1 ( 1 )   2017

  • がん免疫療法-What’s now and what’s next?-第4章 次世代がん免疫療法へのチャレンジ 9.代謝制御によるT細胞機能調節

    榮川伸吾, 鵜殿平一郎

    遺伝子医学MOOK   ( 31 )   2017

  • 2型糖尿病におけるメトホルミンの免疫機能への影響

    野島一郎, 榮川伸吾, 宮本聡, 勅使川原早苗, 利根淳仁, 中司敦子, 江口潤, 四方賢一, 鵜殿平一郎, 和田淳

    糖尿病(Web)   60 ( Suppl )   2017

  • 免疫チェックポイントとがん免疫治療 6.代謝免疫から見るがん免疫治療の新展開

    榮川伸吾, 鵜殿平一郎

    血液フロンティア   27 ( 11 )   2017

  • 2型糖尿病薬メトホルミンはCD8T細胞のアミノ酸代謝および好気的解糖を促進し抗腫瘍作用を示す

    榮川 伸吾, 友信 奈保子, 山下 奈穂子, 渡邉 元嗣, 木村 裕司, 國定 勇希, 上原 健敬, 山崎 千尋, 福田 真嗣, 長谷 耕二, 鵜殿 平一郎

    日本癌学会総会記事   75回   J - 3066   2016.10

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  • 抗PD-1抗体治療後BRAF阻害療法中の進行期メラノーマ患者に生じた原田病 抗PD-1投与前後の免疫応答を含めて

    岩月 啓氏, 山崎 修, 加持 達弥, 濱田 利久, 森実 真, 立川 聖子, 松尾 俊彦, 栄川 伸吾, 鵜殿 平一郎

    西日本皮膚科   78 ( 5 )   554 - 554   2016.10

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  • 抗PD-1抗体'ニボルマブ'治療を受けた悪性黒色腫患者における末梢血CD8T細胞の多機能性解析

    木村 裕司, 榮川 伸吾, 友信 奈保子, 渡邉 元嗣, 鵜殿 平一郎

    日本癌学会総会記事   75回   P - 3216   2016.10

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  • 骨肉腫における腫瘍浸潤骨髄球型細胞を介したメトホルミンの抗腫瘍効果

    上原 健敬, 榮川 伸吾, 國定 勇希, 渡邉 元嗣, 友信 奈保子, 吉田 晶, 藤原 智洋, 国定 俊之, 尾崎 敏文, 鵜殿 平一郎

    日本癌学会総会記事   75回   P - 3220   2016.10

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  • 癌患者由来末梢血CD8+T細胞における糖代謝の障害

    渡邉 元嗣, 榮川 伸吾, 友信 奈保子, 木村 裕司, 上原 健敬, 國定 勇希, 豊岡 伸一, 三好 新一郎, 鵜殿 平一郎

    日本癌学会総会記事   75回   P - 1161   2016.10

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  • メトホルミンは腫瘍局所で多機能性エフェクターT細胞を維持させるためにグルコースを必要とする

    友信 奈保子, 榮川 伸吾, 賀 芳, 山下 奈穂子, 渡邉 基嗣, 木村 裕司, 國定 勇希, 上原 健敬, 鵜殿 平一郎

    日本癌学会総会記事   75回   P - 1162   2016.10

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  • Metforminは腫瘍内骨髄球系細胞の代謝を制御し骨肉腫形成を抑制する

    上原 健敬, 榮川 伸吾, 小松原 将, 森田 卓也, 杉生 和久, 魚谷 弘二, 大森 敏規, 吉田 晶, 藤原 智洋, 武田 健, 国定 俊之, 鵜殿 平一郎, 尾崎 敏文

    日本整形外科学会雑誌   90 ( 8 )   S1555 - S1555   2016.8

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  • メトホルミンの骨肉腫に対する免疫を介した抗腫瘍効果

    上原 健敬, 榮川 伸吾, 小松原 将, 森田 卓也, 杉生 和久, 魚谷 弘二, 吉田 晶, 藤原 智洋, 武田 健, 国定 俊之, 鵜殿 平一郎, 尾崎 敏文

    日本整形外科学会雑誌   90 ( 6 )   S1259 - S1259   2016.6

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  • 抗PD-1抗体とメトホルミン併用による抗腫瘍効果の検討

    西田 充香子, 周 悦, 榮川 伸吾, 山崎 千尋, 一柳 朋子, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   20回   160 - 160   2016.6

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  • 2型糖尿病薬メトホルミンはCD8T細胞のアミノ酸代謝および好気的解糖を促進し抗腫瘍作用を示す

    榮川 伸吾, 友信 奈保子, 賀 芳, 山下 奈穂子, 渡邉 元嗣, 木村 裕司, 野島 一郎, 國定 勇希, 上原 健敬, 山崎 千尋, 長谷 耕二, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   20回   148 - 148   2016.6

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  • 2型糖尿病治療薬メトホルミンのヒト末梢血CD8T細胞への影響

    渡邉 元嗣, 榮川 伸吾, 友信 奈保子, 野島 一郎, 木村 裕司, 上原 健敬, 國定 勇希, 豊岡 伸一, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   20回   150 - 150   2016.6

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  • がんの細胞生物学とケミカルバイオロジー T細胞代謝制御によるがん免疫療法

    榮川 伸吾, 友信 奈保子, 賀 芳, 國定 勇希, 上原 健敬, 渡邉 元嗣, 野島 一郎, 木村 裕司, 鵜殿 平一郎

    日本細胞生物学会大会講演要旨集   68回   37 - 37   2016.5

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  • 【最新のがん免疫療法】メトホルミンによる抗腫瘍効果

    榮川 伸吾, 鵜殿 平一郎

    医薬ジャーナル   52 ( 4 )   1065 - 1070   2016.4

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    近年、2型糖尿病薬メトホルミンは抗腫瘍作用があるとの報告があり、岡山大学ではマウス腫瘍移植モデルにおいて、その抗腫瘍作用は免疫系、特にCD8 T細胞の機能を介した作用であることを報告している。腫瘍内でCD8 T細胞の多くはアポトーシスを起こし、機能も低下しているが、メトホルミン投与によりアポトーシスが抑制され、高機能なエフェクターメモリー型のCD8 T細胞が誘導される。その作用機序としては、AMPK(AMP活性化プロテインキナーゼ)の活性化を介した解糖系(糖代謝)の制御が重要ではないかと考えられる。現在、代謝と免疫応答の関係は非常に注目されたトピックスであり、効果的ながん免疫治療を考える上でも代謝の観点からのアプローチは必要であろう。本邦では、糖尿病薬メトホルミンについて、またその抗腫瘍作用の機序、糖代謝とT細胞応答、T細胞疲弊の関係について言及したい。(著者抄録)

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  • 複合がん免疫療法の時代来る【メトホルミンによる腫瘍微小環境の代謝改変】

    鵜殿平一郎

    月刊細胞   48 ( 13 )   2016

  • がん免疫療法 腫瘍免疫学の最新知見から治療法のアップデートまで 第I部 腫瘍免疫応答の基本とその制御メカニズム 第1章 腫瘍免疫における免疫細胞と免疫分子 1.腫瘍免疫におけるT細胞-免疫疲弊とその代謝制御を中心に

    西田充香子, 榮川伸吾, 鵜殿平一郎

    実験医学   34 ( 12 )   2016

  • 酸化ストレスはメトホルミンによる抗腫瘍効果を誘導する

    西田充香子, 周悦, 山崎千尋, 榮川伸吾, 鵜殿平一郎

    臨床ストレス応答学会大会抄録集   11th   2016

  • メトホルミン服用における健常人および肺癌患者のCD8T細胞の多機能性調査

    鵜殿平一郎, 豊岡伸一, 榮川伸吾

    大和証券ヘルス財団研究業績集   39   2016

  • 肺がんの免疫治療

    鵜殿 平一郎

    呼吸器内科   28 ( 6 )   488 - 493   2015.12

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  • プロテオスタシス制御と疾患 メトホルミンは腫瘍局所浸潤CD8T細胞の解糖を促進する

    鵜殿 平一郎

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   88回・38回   [1W16 - 5]   2015.12

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  • 腫瘍局所のmyeloid-derived suppressor cells(MDSCs)に与えるメトホルミン投与の効果

    上原 健敬, 榮川 伸吾, 國定 勇希, 渡邉 元嗣, 一柳 朋子, 山崎 千尋, 尾崎 敏文, 鵜殿 平一郎

    日本癌学会総会記事   74回   P - 2109   2015.10

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  • 免疫疲弊T細胞に対するメトホルミンによる機能改善の検討

    渡邉 元嗣, 榮川 慎吾, Zhang Feifei, 野島 一郎, 國定 勇希, 上原 健敬, 豊岡 伸一, 鵜殿 平一郎

    日本癌学会総会記事   74回   P - 1257   2015.10

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  • メトホルミンは腫瘍環境下においてCD8陽性エフェクターメモリー細胞の解糖系を亢進する

    榮川 伸吾, 庄 緋菲, 山下 奈穂子, 國定 勇希, 上原 健敬, 渡邉 元嗣, 小西 宏武, 近藤 智子, 西田 充香子, 一柳 朋子, 山崎 千尋, 鵜殿 平一郎

    日本癌学会総会記事   74回   J - 1165   2015.10

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  • メトホルミンは腫瘍局所における制御性T細胞の細胞死と抑制能を調節する

    國定 勇希, 榮川 伸吾, 銅前 昇平, 上原 健敬, 渡邉 元嗣, 山崎 千尋, 一柳 朋子, 佐々木 朗, 鵜殿 平一郎

    日本癌学会総会記事   74回   P - 2114   2015.10

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  • 骨肉腫におけるmyeloid derived suppressor cell(MDSC)に対するmetforminの作用の検討

    上原 健敬, 榮川 伸吾, 藤原 智洋, 杉生 和久, 魚谷 弘二, 大森 敏規, 吉田 晶, 武田 健, 国定 俊之, 鵜殿 平一郎, 尾崎 敏文

    日本整形外科学会雑誌   89 ( 8 )   S1670 - S1670   2015.9

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  • マウス骨肉腫におけるmyeloid derived suppressor cellsとmetforminの作用

    上原 健敬, 榮川 伸吾, 杉生 和久, 魚谷 弘二, 大森 敏規, 山川 泰明, 吉田 晶, 藤原 智洋, 武田 健, 国定 俊之, 鵜殿 平一郎, 尾崎 敏文

    日本整形外科学会雑誌   89 ( 6 )   S1238 - S1238   2015.6

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  • これからのがん免疫療法と今後の展望

    清原 祥夫, 山崎 直也, 宇原 久, 福島 聡, 山口 研成, 室 圭, 山本 信之, 里内 美弥子, 瀬戸 貴司, 井上 彰, 後藤 功一, 鵜殿 平一郎, 西川 博嘉, 山中 竹春

    Immuno-Oncology Frontier   1 ( 1 )   14 - 21   2015.1

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  • がんと免疫

    鵜殿 平一郎

    Immuno-Oncology Frontier   1 ( 1 )   6 - 9   2015.1

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  • 免疫チェックポイントの基礎と臨床 T細胞の免疫疲弊と免疫チェックポイント分子

    榮川伸吾, 鵜殿平一郎

    最新医学   70 ( 3 )   2015

  • がんの免疫療法 メトホルミンは腫瘍微小環境のCD8T細胞の免疫疲弊を解除する(Cancer immunotherapy Metformin-induced reversion of exhausted CD8T cells in tumor microenvironment)

    鵜殿 平一郎, 榮川 伸吾

    日本癌学会総会記事   73回   CS5 - 3   2014.9

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  • メトホルミンは腫瘍浸潤CD8T細胞においてエフェクターメモリー細胞を誘導し、多機能性を付与する(Metformin induced tumor infiltrating CD8 T-cells with effector memory phenotype and multi-functional reversion)

    榮川 伸吾, 根川 真実, 國定 勇希, 上原 健敬, 一柳 朋子, 山崎 千尋, 鵜殿 平一郎

    日本癌学会総会記事   73回   P - 1250   2014.9

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  • 【がん免疫抑制・免疫疲弊と新規治療】T細胞の免疫疲弊制御とがん免疫治療

    榮川 伸吾, 鵜殿 平一郎

    癌と化学療法   41 ( 9 )   1066 - 1070   2014.9

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    感染症やがんでは、CD8T細胞は繰り返す抗原刺激により疲弊(exhaustion)する。疲弊の過程で抗原特異的なCD8T細胞はしだいにサイトカイン産生能を消失し、最終的にはアポトーシスにより死滅する。また、CD8T細胞は持続的な抗原刺激により、疲弊分子PD-1、CTLA-4、TIM-3、LAG-3を発現する。これら疲弊分子とそのリガンドとの結合により発生する負のシグナルによりCD8T細胞はより機能を消失する。2013年、抗PD-1、抗CTLA-4抗体により悪性黒色腫患者で劇的な腫瘍縮小効果が報告された。このようなCD8T細胞疲弊の制御は、今後のがん治療に新たな展開をもたらすと考えられる。(著者抄録)

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    Other Link: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J00296&link_issn=&doc_id=20140924420004&doc_link_id=%2Fab8gtkrc%2F2014%2F004109%2F004%2F1066-1070%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2014%2F004109%2F004%2F1066-1070%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

  • マウス骨肉腫・軟骨肉腫における免疫抑制細胞MDSCに対するmetforminの作用

    上原 健敬, 榮川 伸吾, 大森 敏規, 山川 泰明, 武田 健, 国定 俊之, 尾崎 敏文, 鵜殿 平一郎

    日本整形外科学会雑誌   88 ( 8 )   S1739 - S1739   2014.8

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  • クロスプレゼンテーションとストレス応答蛋白Hsp

    山崎 千尋, 鵜殿 平一郎

    臨床免疫・アレルギー科   62 ( 1 )   105 - 110   2014.7

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  • TCRディープシーケンスによるNY-ESO-1特異的T細胞のモニタリング

    垣見 和宏, 榮川 伸吾, 磯辺 みどり, 松下 博和, 宮井 まなみ, 細井 亮宏, 藤枝 奈緒, 鵜殿 平一郎, 上中 明子, 中山 睿一

    日本がん免疫学会総会プログラム・抄録集   18回   91 - 91   2014.6

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  • 制御性T細胞解析方法の標準化に向けた多施設共同研究

    長瀬 博次, 和田 尚, 西川 博嘉, 鈴木 進, 平家 勇司, 小嶋 隆嗣, 垣見 和宏, 舩越 建, 飯田 真介, 石田 高司, 佐藤 永一, 鵜殿 平一郎, 岡 三喜男, 中山 睿一, 土岐 祐一郎, 上田 龍三

    日本がん免疫学会総会プログラム・抄録集   18回   97 - 97   2014.6

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  • メトホルミンによる腫瘍局所の免疫疲弊解除

    鵜殿平一郎, 榮川伸吾

    日本生化学会大会(Web)   87th   2014

  • 腫瘍浸潤CD8T細胞の免疫疲弊解除における活性化AMPKの役割

    榮川伸吾, 根川真実, 國定勇希, 國定勇希, 上原健敬, 上原健敬, 一柳朋子, 山崎千尋, 鵜殿平一郎

    日本がん免疫学会総会プログラム・抄録集   18th   2014

  • 小胞体ストレスにより癌細胞アポトーシスを誘導するREIC/Dkk-3遺伝子治療が抗腫瘍免疫に及ぼす影響の検討

    有吉勇一, 有吉勇一, 定平卓也, 定平卓也, 渡部昌実, 那須保友, 榮川伸吾, 山崎千尋, 一柳朋子, 鵜殿平一郎, 公文裕巳

    臨床ストレス応答学会大会抄録集   9th   2014

  • NY-ESO-1f(NY-ESO-1 91-110)ペプチドワクチンによる抗体・CD4・CD8T細胞免疫応答の誘導(Induction of humoral, CD4 and CD8 T cell responses by immunization with a 20-mer NY-ESO-1f(NY-ESO-1 91-110) peptide)

    榮川 伸吾, 垣見 和宏, 磯辺 みどり, 和田 尚, 上中 明子, 葛島 清隆, 西川 博嘉, 鵜殿 平一郎, 岡 三喜男, 中山 睿一

    日本癌学会総会記事   72回   154 - 154   2013.10

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  • Hsp70阻害剤が内在性抗原提示に与える影響とそのメカニズム(The effects of Hsp70 inhibitors on endogenous antigen presentation and its molecular mechanisms)

    山崎 千尋, 水上 修作, 榮川 伸吾, 鵜殿 平一郎

    日本癌学会総会記事   72回   369 - 369   2013.10

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  • 抗原提示細胞膜表面HSP90を標的としたmAbを用いたワクチン開発の基盤的研究(Newly vaccine strategy with mAbs against heat shock protein 90(HSP90) on surface of antigen presenting cell(APC))

    水上 修作, 岡山 容子, 山崎 千尋, 鵜殿 平一郎

    日本癌学会総会記事   72回   356 - 356   2013.10

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  • 腫瘍局所における免疫疲弊CD8+T細胞の機能回復を介したメトホルミンの抗腫瘍効果(Reversion of immune-exhausted tumor infiltrating CD8+T lymphocytes by metformin causes effective anti-tumor immunity)

    西田 充香子, 榮川 伸吾, 水上 修作, 山崎 千尋, 鵜殿 平一郎

    日本癌学会総会記事   72回   362 - 362   2013.10

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  • 抗原提示細胞膜表面HSP90を標的としたmAbを用いたワクチン開発の基盤的研究

    水上 修作, 山崎 千尋, 岡山 容子, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   17回   125 - 125   2013.7

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  • 腫瘍局所における免疫疲弊とその解除による抗腫瘍免疫応答

    鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   17回   36 - 36   2013.7

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  • 免疫チェックポイント制御とがん免疫治療

    鵜殿 平一郎

    岡山医学会雑誌   125 ( 1 )   13 - 18   2013.4

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    がんワクチンによる免疫治療では,如何にCD8T細胞を感作(プライミング)しその数を増やすか(免疫増強)という点に多大の努力が払われて来た.樹状細胞への抗原デリバリーと抗原プロセシング/提示,Toll様受容体などの刺激,即ち自然免疫系の活性化の併用などはそれに該当する.しかし十分に活性化されたT細胞をもってしても癌の拒絶は容易ではない.それには癌組織という特殊な環境が禍している.T細胞は癌塊内に入り込み莫大な数の癌細胞と遭遇する.癌組織内での繰り返す抗原認識の過程でT細胞は疲弊し,次第に本来あるべき機能を喪失していく.この疲弊(exhaustion)と呼ばれる現象は,T細胞に発現する複数の免疫抑制性分子-免疫チェックポイント分子-と腫瘍に発現するそのリガンドの結合によってもたらされる.代表的なチェックポイント分子の機能を抑制し,エフェクターT細胞が疲弊することなくその機能を長く維持できれば,これからのがん免疫治療に飛躍的な進展がみられるかもしれない.(著者抄録)

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  • Heat shock protein阻害剤が内在性抗原提示に与える影響

    山崎千尋, 山下奈穂子, 梶原千晶, 加藤悠, 松本彩, 水上修作, 榮川伸吾, 鵜殿平一郎

    臨床ストレス応答学会大会抄録集   8th   2013

  • 腫瘍局所における免疫疲弊CD8T細胞の機能回復を介したメトホルミンの抗腫瘍効果

    榮川伸吾, 西田充香子, 水上修作, 山崎千尋, 國定勇希, 上原健敬, 有吉勇一, 鵜殿平一郎

    日本がん免疫学会総会プログラム・抄録集   17th   2013

  • Heat shock protein阻害剤が内在性抗原提示に与える影響

    山崎千尋, 山下奈穂子, 松本彩, 水上修作, 榮川伸吾, 鵜殿平一郎

    日本がん免疫学会総会プログラム・抄録集   17th   2013

  • 遺伝子改変マウスを用いた個体レベルのHsp90研究

    鵜殿平一郎, 榮川伸吾, 山崎千尋, 一柳朋子, 水上修作, 一柳健司

    日本生化学会大会(Web)   86th   2013

  • 熱ショックタンパク質と交差抗原提示機構

    鵜殿 平一郎

    生化学   84 ( 10 )   829 - 839   2012.10

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    これまでの熱ショックタンパク質(HSP)研究の主流は生化学的手法によるものあるいは特定の細胞株を用いた実験系が大多数であったが、遺伝子改変マウスの作製が進むにつれその意義が生体レベルでも明らかにされるようになってきた。HSPは細胞をストレスから防御する、ということがその第一義的な役割だが、免疫系においてはがん抗原やウイルス抗原の抗原プロセシングひいては主要組織適合抗原(MHC)による抗原提示に重要な役割をもつことが示唆されている。凝集性を帯び始めたタンパク質はHSPに認識され、抗原プロセシングの過程に組み込まれる。Hsp90αKOマウス作製とそれを用いた研究により、これまでの「HSPと免疫研究」に確信と前進がもたらされた。遺伝子改変マウスを用いた実験結果と生化学的解析さらには分子イメージングから得られるHSPの免疫系、特に交差抗原提示機構における役割について最新の知見を論述・考察したい。(著者抄録)

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  • 樹状細胞膜表面に存在するHsp90はシャペロン複合体を構成し、抗Hsp90抗体の迅速な取り込みに関与する(Hsp90 existing on DC surface forms a chaperone complex and is involved in internalization of an antibody to Hsp90)

    山崎 千尋, 水上 修作, 鵜殿 平一郎

    日本癌学会総会記事   71回   113 - 113   2012.8

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  • 【樹状細胞の機能と免疫応答】樹状細胞による交差抗原提示とHSP

    山崎 千尋, 鵜殿 平一郎

    臨床免疫・アレルギー科   58 ( 2 )   143 - 147   2012.8

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  • 抗原提示細胞膜表面hsp90を標的としたmAbを用いたワクチン開発の基盤的研究(Newly vaccine strategy with mAbs against heat shock protein 90 (hsp90) on surface of antigen presenting cell (APC))

    水上 修作, 山崎 千尋, 鵜殿 平一郎

    日本癌学会総会記事   71回   100 - 100   2012.8

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  • グルタミン酸-ロイシン-アルギニンモチーフ結合ペプチドによる制御性T細胞の遊走阻害(Inhibition of regulatory T-cell migration by ELR motif-binding peptide)

    榮川 伸吾, 黒瀬 浩史, 松本 博文, 磯辺 みどり, 上中 明子, 水上 修作, 山崎 千尋, 大植 祥弘, 岡 三喜男, 鵜殿 平一郎, 中山 睿一

    日本癌学会総会記事   71回   428 - 428   2012.8

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  • 抗原提示細胞膜表面hsp90を標的としたmAbを用いたワクチン開発の基盤的研究

    水上 修作, 山崎 千尋, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   16回   76 - 76   2012.7

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  • がん免疫の新しい仕組みを探る がんワクチン投与患者における抗原特異的CD8 T細胞の免疫応答の解析

    榮川 伸吾, 水上 修作, 山崎 千尋, 垣見 和宏, 中山 睿一, 鵜殿 平一郎

    Cytometry Research   22 ( Suppl. )   36 - 36   2012.6

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  • HSP70とHSP90がクロスプレゼンテーションに与える影響は異なる

    山崎千尋, 水上修作, 榮川伸吾, 鵜殿平一郎

    臨床ストレス応答学会大会抄録集   7th   2012

  • FcRγ依存性に発現する樹状細胞膜表面シャペロン複合体

    鵜殿平一郎, 水上修作, 山崎千尋, 榮川伸吾

    日本がん免疫学会総会プログラム・抄録集   16th   2012

  • 造血・免疫系形成 胸腺上皮細胞株におけるbeta5サブユニットの発現プロファイル(Expression profiles of beta5 subunits in thymic epithelial cell lines)

    笠井 道之, 鵜殿 平一郎, 高浜 洋介

    日本免疫学会総会・学術集会記録   40   216 - 216   2011.11

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  • mAbを用いた抗原提示細胞膜表面HSP90の解析とワクチンの可能性検討(mAbs against Heat Shock Protein 90 (HSP90) on surface of antigen presenting cell)

    水上 修作, 松浦 貴志, 梶原 千晶, 宇田 静葉, 鵜殿 平一郎

    日本癌学会総会記事   70回   393 - 393   2011.9

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  • クロスプレゼンテーションには細胞質トランスロケーターとしてのHSP90が必須である(Dendritic cells require HSP90 as a cytosolic translocator of extracellular antigen for cross-presentation)

    加藤 悠, 今井 孝, 梶原 千晶, 水上 修作, 石下 郁夫, 一柳 朋子, 疋田 正喜, 王 継揚, 鵜殿 平一郎

    日本癌学会総会記事   70回   218 - 218   2011.9

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  • 生物の「生き残り」を担う戦略分子HSPと免疫防御

    鵜殿 平一郎

    岡山医学会雑誌   123 ( 2 )   175 - 175   2011.8

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  • クロスプレゼンテーションには細胞質トランスロケーターとしてのHSP90が必須である

    加藤 悠, 今井 孝, 梶原 千晶, 水上 修作, 石下 郁夫, 一柳 朋子, 引田 正喜, 王 継揚, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   15回   71 - 71   2011.6

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  • mAbを用いた抗原提示細胞膜表面HSP90の解析とワクチンの可能性検討

    水上 修作, 松浦 貴志, 梶原 千晶, 宇田 静葉, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   15回   69 - 69   2011.6

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  • 抗原提示細胞の細胞膜表面HSP90を標的とするモノクローナル抗体を用いたクロスプレゼンテーション及び細胞性免疫の誘導(mAb-mediated targeting of surface HSP90 on APCs enables efficient cross-presentation and cytotoxic T cell immunity)

    水上 修作, 菅原 英俊, 梶原 千晶, 宇田 静葉, 今井 孝, 鵜殿 平一郎

    日本癌学会総会記事   69回   398 - 398   2010.8

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  • 抗原提示細胞膜表面Hsp90に対するmAbワクチンの可能性検討

    水上 修作, 菅原 英俊, 梶原 千晶, 宇田 静葉, 今井 孝, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   14回   76 - 76   2010.7

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  • ヒト26Sプロテアソームのリン酸化による機能調節

    木村 弥生, 永田 佳代子, 菅原 英俊, 井野 洋子, 野村 文子, 小原 收, 鵜殿 平一郎, 平野 久

    生物物理化学   54 ( Suppl. )   31 - 31   2010.7

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  • メラノーマ抗原TRP2産生における、PA28-20S、26Sプロテアソームの関与(Processing of melanoma antigen TRP2 is determined by a net-balance between activities of PA28-20S and 26S proteasome)

    菅原 英俊, 水上 修作, 今井 孝, 鵜殿 平一郎

    日本癌学会総会記事   68回   292 - 292   2009.8

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  • 熱ショックタンパク質90 クロスプレゼンテーションに於いてエンドソーム内の外来性抗原を細胞質に引き出す駆動力(Heat shock protein 90: a driving force that pulls endosomal exogenous antigen to cytosol in cross-presentation)

    今井 孝, 一柳 朋子, 梶原 千晶, 水上 修作, 菅原 英俊, 鵜殿 平一郎

    日本癌学会総会記事   68回   290 - 290   2009.8

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  • 各種特異的抗体を用いた樹状細胞表面の熱ショック蛋白質(HSP)90の解析(Analysis of surface Heat Shock Protein(HSP) 90 on dendritic cells with several types of specific antibodies)

    水上 修作, 今井 孝, 菅原 英俊, 鵜殿 平一郎

    日本癌学会総会記事   68回   291 - 291   2009.8

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  • 腫瘍抗原 メラノーマ抗原TRP2産生における、PA28-20S、26Sプロテアソームの関与

    菅原 英俊, 水上 修作, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   13回   77 - 77   2009.6

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  • 樹状細胞 新たに作成した抗体を用いた細胞膜表面Hsp90の解析

    水上 修作, 今井 孝, 菅原 英俊, 梶原 千晶, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   13回   50 - 50   2009.6

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  • 樹状細胞 クロスプレゼンテーションにおけるHsp90の関与

    今井 孝, 一柳 朋子, 梶原 千晶, 水上 修作, 菅原 英俊, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   13回   51 - 51   2009.6

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  • 【腫瘍の免疫回避機構と抗腫瘍免疫の誘導】熱ショックタンパク質を用いた抗原のクロスプレゼンテーション

    水上 修作, 鵜殿 平一郎

    臨床免疫・アレルギー科   50 ( 4 )   394 - 399   2008.10

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  • 2タイプの制御性T細胞の解除による癌免疫寛容の克服と腫瘍拒絶

    塚田 晃三, 戸田 正博, 鵜殿 平一郎, 河上 裕, 高橋 公正, 道下 正貴, 由井 克之

    日本獣医学会学術集会講演要旨集   146回   251 - 251   2008.9

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  • TLR-MyD88を介さない結核菌hsc70依存性T細胞クロスプライミング(MyD88-TLR independent cross-priming of CD8+ T cells by Mycobacterium hsp 70)

    水上 修作, 梶原 千晶, 鵜殿 平一郎

    日本癌学会総会記事   67回   492 - 492   2008.9

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  • TLR-MyD88を介さないHSP依存性T細胞クロスプレゼンテーション

    水上 修作, 梶原 千晶, 鵜殿 平一郎

    基盤的癌免疫研究会総会抄録   12回   48 - 48   2008.6

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  • 腫瘍免疫、移植免疫 HSP介在性クロスプライミングにおけるMyD88分子の役割

    水上 修作, 鵜殿 平一郎

    Annual Review免疫   2008   210 - 216   2007.11

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  • HspによるMyD88非依存性クロスプレゼンテーション(HSP-mediated MyD88 independent cross-priming)

    水上 修作, 山野 武寿, 改正 恒康, 由井 克之, 鵜殿 平一郎

    日本癌学会総会記事   66回   158 - 158   2007.8

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  • IL-18はPA28-20Sプロテアソーム依存性にアポトーシスを誘導する

    山野 武寿, 鵜殿 平一郎

    基盤的癌免疫研究会総会抄録   11回   57 - 57   2007.5

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  • 【抗原提示の機序をめぐって】Hspによる抗原提示能の増強とその機序

    山野 武寿, 鵜殿 平一郎

    臨床免疫・アレルギー科   47 ( 2 )   149 - 156   2007.2

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  • MHC、抗原細胞提示機構 IFNγによるMHCクラスI発現機構の調節

    山野 武寿, 鵜殿 平一郎

    Annual Review免疫   2007   36 - 44   2006.12

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  • 腫瘍抗原融合heat shock protein(hsp)による抗腫瘍効果の検討

    水上 修作, 梶原 千晶, 山野 武寿, 三宅 靖延, 田中 正人, 改正 恒康, 由井 克之, 鵜殿 平一郎

    日本癌学会総会記事   65回   238 - 238   2006.9

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  • 熱ショック蛋白hsp90によるプロテアソームを介するMHCクラスI抗原提示制御システムの解析

    山野 武寿, 一柳 朋子, 水上 修作, 鵜殿 平一郎

    日本癌学会総会記事   65回   316 - 316   2006.9

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  • 癌ワクチンNY-ESO-1 p157-175/HSP70融合蛋白が誘導するTh1/Th2バランス

    伊藤 信一郎, 永田 康浩, 進 誠也, 松尾 光敏, 鵜殿 平一郎, 兼松 隆之

    日本癌学会総会記事   65回   318 - 318   2006.9

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  • 癌免疫療法におけるアジュバントの新知見 Heat Shock Proteinをアジュバントに用いたワクチンの有用性

    水上 修作, 山野 武寿, 鵜殿 平一郎

    Surgery Frontier   13 ( 3 )   294 - 296   2006.9

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  • 腫瘍抗原融合heat shock proteinによる抗腫瘍効果の検討

    水上 修作, 梶原 千晶, 山野 武寿, 三宅 靖延, 田中 正人, 改正 恒康, 由井 克之, 鵜殿 平一郎

    基盤的癌免疫研究会総会抄録   10回   36 - 36   2006.6

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  • 熱ショック蛋白hsp90によるプロテアソームを介するMHCクラスI抗原提示制御システムの解析

    山野 武寿, 一柳 朋子, 水上 修作, 鵜殿 平一郎

    基盤的癌免疫研究会総会抄録   10回   34 - 34   2006.6

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  • NY-ESO-1 p157-165/HSP70融合蛋白による癌ワクチン臨床応用のための樹状細胞誘導法の確立

    伊藤 信一郎, 永田 康浩, 進 誠也, 松尾 光敏, 鵜殿 平一郎, 兼松 隆之

    日本外科学会雑誌   107 ( 臨増2 )   604 - 604   2006.3

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  • Heat shock protein結合ペプチドワクチンのVivoにおける有効性の検討

    水上 修作, 山野 武寿, 由井 克之, 鵜殿 平一郎

    日本免疫学会総会・学術集会記録   35   263 - 263   2005.11

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  • 熱ショック蛋白Hsp90はプロテアソームの構築及びそのペプチド切断活性を制御する

    山野 武寿, 水上 修作, 鵜殿 平一郎

    日本免疫学会総会・学術集会記録   35   264 - 264   2005.11

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  • 熱ショック蛋白Hsp90はプロテアソームの構築及びそのペプチド切断活性を制御する

    山野 武寿, 水上 修作, 鵜殿 平一郎

    日本癌学会総会記事   64回   354 - 354   2005.9

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  • キャップ分子の異なるプロテアソーム複合体の構造機能解析

    水上 修作, 山野 武寿, 鵜殿 平一郎

    日本癌学会総会記事   64回   352 - 352   2005.9

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  • 樹状細胞における融合蛋白NY-ESO-1 epitope157-165/hsc70の取り込みと免疫学的解析

    伊藤 信一郎, 永田 康浩, 進 誠也, 松尾 光敏, 鵜殿 平一郎, 兼松 隆之

    日本癌学会総会記事   64回   485 - 485   2005.9

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  • 新時代のがん免疫研究 プロテアソームとストレス蛋白の相互作用による抗原プロセシング

    鵜殿 平一郎, 水上 修作, 山野 武寿

    日本癌学会総会記事   64回   508 - 508   2005.9

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  • 熱ショック蛋白Hsp90はプロテアソームの構築及びそのペプチド切断活性を抑制する

    山野 武寿, 水上 修作, 鵜殿 平一郎

    基盤的癌免疫研究会総会抄録   9回   64 - 64   2005.6

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  • Heat shock protein結合ペプチドワクチンのVivoにおける有効性の検討

    水上 修作, 梶原 千晶, 山野 武寿, 鵜殿 平一郎

    基盤的癌免疫研究会総会抄録   9回   63 - 63   2005.6

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  • ヒト癌・精巣抗原エピトープとストレス蛋白hsc70の融合蛋白の樹状細胞における抗原提示経路の解明

    進 誠也, 永田 康浩, 伊藤 信一郎, 松尾 光敏, 鵜殿 平一郎, 由井 克之, 兼松 隆之

    日本外科学会雑誌   106 ( 臨増 )   358 - 358   2005.4

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  • 【免疫2005】抗原認識 タンパク質のプロセシングにおけるプロテアソームと分子シャペロンの相互作用

    鵜殿 平一郎

    Molecular Medicine   41 ( 臨増 )   90 - 97   2004.12

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  • プロテアソーム活性化分子PA28遺伝子導入によるMHCクラスI分子の発現修飾と細胞死誘導

    山野 武寿, 水上 修作, 吉田 由紀, 鵜殿 平一郎

    日本免疫学会総会・学術集会記録   34   182 - 182   2004.11

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  • 抗腫瘍免疫におけるトレランス解除の新しい治療プログラム

    塚田 晃三[大楠], 本間 季里, 鵜殿 平一郎, 由井 克之

    日本免疫学会総会・学術集会記録   34   142 - 142   2004.11

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  • Hsp70はプロテアソームに作用しMHCクラスI抗原提示を制御する

    水上 修作, 山野 武寿, 吉田 由紀, 鵜殿 平一郎

    日本免疫学会総会・学術集会記録   34   181 - 181   2004.11

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  • LPS応答性におけるinterferon regulatory factor-4(IRF-4)の機能解析 LPS刺激によるJNK活性化におけるIRF-4の役割

    本間 季里, 塚田 晃三[大楠], 都田 真奈, 鵜殿 平一郎, 鈴木 章一, 熊取 厚志, 松山 俊文, 由井 克之

    日本免疫学会総会・学術集会記録   34   53 - 53   2004.11

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  • 分子シャペロンhsp70はhsp40と共にプロテアソーム機能を制御する

    吉田 由紀, 山野 武寿, 水上 修作, 鵜殿 平一郎

    日本免疫学会総会・学術集会記録   34   181 - 181   2004.11

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  • プロテアソーム活性化分子PA28遺伝子導入による腫瘍細胞死の誘導,及びそのメカニズム解析

    山野 武寿, 水上 修作, 鵜殿 平一郎

    日本癌学会総会記事   63回   513 - 513   2004.9

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  • 尿中プロテアーゼ抵抗性蛋白質検出によるプリオン病早期診断の試み(続報)

    古川 ひさ子, 堂浦 克美, 調 漸, 山本 一男, 鵜殿 平一郎, 伊藤 敬, 片峰 茂, 丹羽 正美

    Dementia Japan   18 ( 2 )   139 - 139   2004.8

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  • スギ花粉症特異的ワクチン療法 ストレス蛋白とスギ花粉抗原の複合体を用いたワクチン作製

    清水(吉田) 由紀, 鵜殿 平一郎

    臨床免疫   42 ( 2 )   245 - 249   2004.8

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  • プロテアソーム活性化分子PA28遺伝子導入による腫瘍細胞死の誘導,及びそのメカニズム解析

    山野 武寿, 水上 修作, 鵜殿 平一郎

    基盤的癌免疫研究会総会抄録   8回   37 - 37   2004.7

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  • ヒト癌・精巣抗原エピトープとストレス蛋白hsc70の融合蛋白による癌ワクチン作製と臨床応用

    進 誠也, 永田 康浩, 伊藤 信一郎, 松尾 光敏, 鵜殿 平一郎, 由井 克之, 兼松 隆之

    日本外科学会雑誌   105 ( 臨増 )   589 - 589   2004.3

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  • 【免疫2004】抗原認識 シャペロン分子(HSPs)と抗原プロセッシング

    鵜殿 平一郎, 水上 修作, 山野 武寿

    Molecular Medicine   40 ( 臨増 )   57 - 64   2003.12

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    細胞は内在性抗原と外来性抗原を分解するために,各々ユビキチン-プロテアソーム系とライソゾーム系を具備している.しかし,抗原側からみるとこの両者は隔絶されたものではなく,互いに行きかうことが可能であり,独特の連続した分解システムを構築している.de novo合成されたMHCクラスI分子だけではなく,細胞膜に存在するMHCクラスI分子でもリサイクルシステムにより内在性及び外来性抗原とアクセスできるようである.シャペロン分子(HSPs)は,この2つの分解系にタンパク質を輸送する役割を担い,MHCクラスI,II抗原提示経路に予想を上回るダイナミズムを与えている

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  • プロテアソーム活性化分子PA28遺伝子導入による腫瘍細胞死の誘導,及びそのメカニズム解析

    山野 武寿, 水上 修作, 由井 克之, 鵜殿 平一郎

    日本免疫学会総会・学術集会記録   33   118 - 118   2003.11

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  • LPS応答性におけるinterferon regulatory factor-4(IRF-4)の機能解析

    本間 季里, 鵜殿 平一郎, 河野 友子, 竹森 利忠, 鈴木 章一, 熊取 厚志, 松山 俊文, 由井 克之

    日本免疫学会総会・学術集会記録   33   125 - 125   2003.11

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  • p38α scaffold分子TAB1によるT細胞アナジーの維持機構

    塚田 晃三[大楠], 冨永 典男, 鵜殿 平一郎, 由井 克之

    日本免疫学会総会・学術集会記録   33   45 - 45   2003.11

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  • プロテアソーム活性化分子PA28遺伝子導入による腫瘍細胞死の誘導,及びそのメカニズム解析

    山野 武寿, 水上 修作, 由井 克之, 鵜殿 平一郎

    日本癌学会総会記事   62回   195 - 195   2003.8

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  • ヒト癌・精巣抗原NY-ESO-1由来抗原エピトープとhsc70の融合蛋白の作製と樹状細胞による抗原エピトープの提示

    進 誠也, 永田 康浩, 鵜殿 平一郎, 兼松 隆之

    日本癌学会総会記事   62回   173 - 173   2003.8

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  • プロテアソーム活性化分子PA28遺伝子導入による腫瘍細胞死の誘導,及びそのメカニズム解析

    山野 武寿, 水上 修作, 由井 克之, 鵜殿 平一郎

    基盤的癌免疫研究会総会抄録   7回   35 - 35   2003.7

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  • MHCクラスI結合ペプチドの処理におけるPA28とhsp90

    山野 武寿, 由井 克之, 鵜殿 平一郎

    臨床免疫   39 ( 4 )   464 - 469   2003.4

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  • 内在性抗原のプロセシング機構 PA28,hsp90はいかに機能するのか?

    鵜殿 平一郎, 山野 武寿, 由井 克之

    細胞工学   22 ( 1 )   70 - 74   2002.12

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  • 侵襲と生体反応 MHCクラスI分子とクロスプレゼンテーション

    由井 克之, 本間 季里, 鵜殿 平一郎

    Surgery Frontier   9 ( 4 )   345 - 348   2002.12

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  • Hsc70-エピトープ融合蛋白によるクロスプレゼンテーション-hsc70の抗原提示細胞への取り込み様式

    本間 季里, 鵜殿 平一郎, 由井 克之

    日本免疫学会総会・学術集会記録   32   56 - 56   2002.10

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  • CD4+T細胞のアナジー維持シグナルの解除;p38キナーゼの抑制によるERKの活性化

    塚田 晃三[大楠], 冨永 典男, 鵜殿 平一郎, 由井 克之

    日本免疫学会総会・学術集会記録   32   257 - 257   2002.10

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  • MHCクラスI抗原提示におけるPA28の効果にはハプロタイプにより正の効果と負の効果が存在する

    山野 武寿, 村田 茂穂, 新原 直樹, 田中 紀章, 千葉 智樹, 田中 啓二, 由井 克之, 鵜殿 平一郎

    日本免疫学会総会・学術集会記録   32   215 - 215   2002.10

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  • CD4 T細胞の活性化・機能分化におけるIRF-4の役割

    冨永 典男, 塚田 晃三[大楠], 鵜殿 平一郎, 松山 俊文, 由井 克之

    日本免疫学会総会・学術集会記録   32   232 - 232   2002.10

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  • インターフェロンγ処理時のクラスI Kd(Dd)の発現低下はPA28を介する

    山野 武寿, 村田 茂穂, 新原 直樹, 田中 紀章, 千葉 智樹, 田中 啓二, 由井 克之, 鵜殿 平一郎

    日本癌学会総会記事   61回   129 - 129   2002.10

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  • MHV感染による研究障害例 : マラリア原虫感染実験例

    川畑 優子, 本間 季里, 鵜殿 平一郎, 上田 正勝, 由井 克之

    実験動物と環境 = Laboratory animal and environment   10 ( 1 )   12 - 17   2002.4

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  • 外来性抗原のMHCクラスI分子へのクロスプレゼーション

    臨床免疫   37(2), 138-142   2002

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  • 外来性抗原のクロスプレゼンテーションとHSP

    Ann. Rev. 免疫 2003   32, 40-49   2002

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  • IL-10産生in vivoT細胞アナジーとp38MAPキナーゼの制御

    塚田 晃三[大楠], 冨永 典男, 鵜殿 平一郎, 由井 克之

    日本免疫学会総会・学術集会記録   31   246 - 246   2001.12

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  • プロテアソーム調節分子PA28及びそのドミナントネガティブ分子によるMHC class I抗原提示の機能解析

    山野 武寿, 新原 直樹, 田中 紀章, 田中 啓二, 由井 克之, 鵜殿 平一郎

    日本免疫学会総会・学術集会記録   31   167 - 167   2001.12

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  • CD4 T細胞の活性化・機能分化におけるIRF-4の役割

    冨永 典男, 塚田 晃三[大楠], 鵜殿 平一郎, 松山 俊文, 由井 克之

    日本免疫学会総会・学術集会記録   31   52 - 52   2001.12

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  • MSP1/hsc70融合蛋白の抗マラリアワクチン効果

    川畑 優子, 本間 季里, 鵜殿 平一郎, 上田 正勝, 迎 寛, 河野 茂, 由井 克之

    日本免疫学会総会・学術集会記録   31   122 - 122   2001.12

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  • Hsc70-エピトープ融合蛋白によるクロスプレゼンテーション TAP非依存性抗原提示経路の解析

    本間 季里, 鵜殿 平一郎, 由井 克之

    日本免疫学会総会・学術集会記録   31   199 - 199   2001.12

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  • CD4+T細胞認識癌抗原ペプチドの抗腫瘍効果に及ぼす影響について:hsc70との融合分子を用いた解析

    石川 博士, 山野 武寿, 片山 一朗, 由井 克之, 鵜殿 平一郎

    日本癌学会総会記事   60回   606 - 606   2001.9

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  • プロテアソーム調節分子PA28及びそのドミナントネガティブ分子によるMHC class I抗原提示の機能解析

    山野 武寿, 新原 直樹, 田中 紀章, 田中 啓二, 由井 克之, 鵜殿 平一郎

    日本癌学会総会記事   60回   191 - 191   2001.9

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  • hsc70-癌抗原ペプチド融合蛋白を用いたマウス腫瘍免疫学的治療モデルの検討

    石川 博士, 山野 武寿, 鵜殿 平一郎, 由井 克之, 片山 一朗

    日本研究皮膚科学会年次学術大会・総会プログラム   26回   104 - 104   2001.9

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  • MSP1/hsc70融合蛋白ワクチンによるPlasmodium yoelii原虫感染に対する防御免疫の誘導

    川畑 優子, 門田 淳一, 河野 茂, 鵜殿 平一郎, 上田 正勝, 由井 克之

    感染症学雑誌   75 ( 7 )   618 - 618   2001.7

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  • MSP1/hsc70融合蛋白ワクチンによるPlasmodium yoelii原虫感染に対する防御免疫の誘導

    川畑 優子, 門田 淳一, 河野 茂, 鵜殿 平一郎, 上田 正勝, 由井 克之

    感染症学雑誌   75 ( 臨増 )   90 - 90   2001.2

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  • P183 Induction of the productive immunity against Plasmodium yoelii by MSP1/hsc70 fusion protein vaccine

    KAWABATA Yuko, UDONO Heiichiro, UEDA Masakatsu, KADOTA Junichi, KOHNO Shigeru, YUI Katsuyuki

    Medical Entomology and Zoology   52 ( 0 )   2001

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  • マラリア制圧の分子論的展開とフィールドスタディー・研究集会報告 1 Msp1/hsc70融合蛋白の抗マラリアワクチン効果

    川畑 優子, 本間 季里, 鵜殿 平一郎, 上田 正勝, 由井 克之

    長崎大学熱帯医学研究所共同研究報告集   13   2001

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  • Hsc70-エピトープ融合蛋白によるクロスプレゼンテーション

    本間 季里, 鵜殿 平一郎, 小阪 博, 由井 克之

    日本免疫学会総会・学術集会記録   30   313 - 313   2000.11

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  • CD4+T細胞のアナジー維持におけるp38MAPキナーゼの役割

    塚田 晃三[大楠], 富永 典男, 鵜殿 平一郎, 由井 克之

    日本免疫学会総会・学術集会記録   30   92 - 92   2000.11

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  • Hsc70-癌抗原ペプチド融合蛋白を用いたマウス腫瘍免疫学的治療モデルの検討

    石川 博士, 鵜殿 平一郎, 山野 武寿, 片山 一朗, 由井 克之

    日本免疫学会総会・学術集会記録   30   151 - 151   2000.11

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  • MHCクラスI前駆ペプチドプロセシングにおけるストレス蛋白hsp90及びPA28の役割検討

    山野 武寿, 新原 直樹, 田中 紀章, 田中 啓二, 由井 克之, 鵜殿 平一郎

    日本免疫学会総会・学術集会記録   30   312 - 312   2000.11

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  • マラリア原虫抗原Msp1/マウスhsc70融合蛋白のワクチン効果の解析

    川畑 優子, 鵜殿 平一郎, 上田 正勝, 門田 淳一, 河野 茂, 由井 克之

    日本免疫学会総会・学術集会記録   30   297 - 297   2000.11

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  • Hsc70によるCTL誘導について

    鵜殿 平一郎, 吉村 篤利, 由井 克之

    日本免疫学会総会・学術集会記録   30   167 - 167   2000.11

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  • MHCクラスI前駆ペプチドプロセシングにおけるストレス蛋白hsp90及びPA28の役割検討

    山野 武寿, 新原 直樹, 田中 紀章, 田中 啓二, 由井 克之, 鵜殿 平一郎

    日本癌学会総会記事   59回   452 - 453   2000.9

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  • Hsc-70-癌抗原ペプチド融合蛋白を用いたマウス腫瘍免疫学的治療モデルの検討

    石川 博士, 片山 一朗, 由井 克之, 鵜殿 平一郎

    日本癌学会総会記事   59回   356 - 356   2000.9

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  • 抗腫瘍免疫とHSP

    現代医療   32 ( 5 )   79   2000

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  • マラリアCS蛋白由来CTLエピトープとHsc70の融合分子によるワクチン効果

    鵜殿 平一郎, 上田 正勝, 川畑 優子, 由井 克之

    日本免疫学会総会・学術集会記録   29   256 - 256   1999.10

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  • 肝細胞期に発現されるマラリア原虫抗原の同定とその免疫効果の解析

    川畑 優子, 鵜殿 平一郎, 上田 正勝, 門田 淳一, 河野 茂, 由井 克之

    日本免疫学会総会・学術集会記録   29   253 - 253   1999.10

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  • ナイーブ及びアナジーT細胞の活性化と細胞分裂におけるCD4/CD8細胞の相違

    塚田 晃三[大楠], 鵜殿 平一郎, 安部 良, 由井 克之

    日本免疫学会総会・学術集会記録   29   328 - 328   1999.10

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  • MHCクラスI前駆ペプチドプロセシングにおける熱ショック蛋白質hsp90及びPA28の役割検討

    山野 武寿, 石井 辰明, 新原 直樹, 日伝 晶夫, 田中 紀章, 田中 啓二, 由井 克之, 鵜殿 平一郎

    日本免疫学会総会・学術集会記録   29   106 - 106   1999.10

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  • 自己腫瘍由来熱ショック蛋白質の腫瘍ワクチンと12の可能性

    13   41 - 43   1999

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  • MHCクラスI抗原提示におけるストレス蛋白hsp70の役割解析

    山野 武寿, 鵜殿 平一郎, 石井 辰明, 日伝 晶夫, 田中 紀章, 中山 睿一, 由井 克之

    日本臨床免疫学会会誌   ( 26回抄録集 )   210 - 210   1998.10

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  • トキソプラズマ原虫抗原の血清学的同定,分子クローニングと宿主免疫応答の解析

    川畑 優子, 鵜殿 平一郎, 上田 正勝, 門田 淳一, 河野 茂, 由井 克之

    日本臨床免疫学会会誌   ( 26回抄録集 )   333 - 333   1998.10

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  • 【免疫系はがん細胞を拒絶できるか】抗原提示認識を利用した免疫治療 がん抗原プロセッシングにおけるhspの役割とがんワクチンへの応用

    鵜殿 平一郎

    細胞工学   17 ( 8 )   1245 - 1250   1998.8

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  • 自己血清により軟骨肉腫で検出された56kDa分子の解析

    藤原 一夫, 鵜殿 平一郎, 国定 俊之, 川井 章, 井上 一, 難波 正義, 中山 睿一

    日本整形外科学会雑誌   72 ( 8 )   s1633 - s1633   1998.8

  • 癌抗原プロセッシングにおけるhspの役割と免疫療法への応用

    細胞工学   8   1245 - 1250   1998

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  • 抗原ペプチド転送とTAP

    臨床免疫   30 ( 9 )   1284 - 1290   1998

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  • 杭原ペプチドのMHC クラスIへの転送分子

    Annual Review免疫97   147 - 153   1997

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  • 腫瘍由来ストレス蛋白結合性ペプチドの解析

    鵜殿 平一郎

    日本癌学会総会記事   55回   108 - 108   1996.9

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  • 熱ショック蛋白と癌免疫

    血液・免疫・腫瘍 BIC Forum   1 ( 1 )   36 - 40   1996

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  • ストレス蛋白(Heat Shock Protein:hsp)と癌免疫

    Biotherapy   10   1286 - 1292   1996

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  • 腫瘍由来熱ショック蛋白結合性ペプチドの解析

    鵜殿 平一郎

    日本癌学会総会記事   54回   319 - 319   1995.9

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  • 腫瘍細胞熱ショック蛋白の抗腫瘍効果における役割-腫瘍拒絶抗原としての熱ショック蛋白

    別冊・医学のあゆみ 免疫疾患-state of aots   239 - 242   1995

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  • 腫瘍細胞由来熱ショック蛋白による抗腫瘍効果

    鵜殿 平一郎

    日本癌学会総会記事   53回   408 - 408   1994.10

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  • T細胞が認識する癌抗原ペプチド

    臨床免疫   26 ( 6 )   617 - 621   1994

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  • 抗CD3mAbのBALBRL♂1白血病に対する増殖抑制効果

    鵜殿 平一郎

    日本癌学会総会記事   50回   247 - 247   1991.8

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  • BALBRL♂1のin vitro及びin vivo増殖に及ぼす抗CD3mAbの抑制効果

    鵜殿 平一郎

    日本免疫学会総会・学術集会記録   20   338 - 338   1990.10

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  • ラット肝移植における長期生着の機構 肝生着ラットにおける細胞傷害性T細胞(OTL)の誘導とその抑制

    山口 淳三, 寺田 正純, 小原 則博, 田中 公朗, 元島 幸一, 角田 司, 三重野 政広, 鵜殿 平一郎, 野口 雄司, 珠玖 洋, 中山 睿一

    移植   25 ( 臨時 )   337 - 337   1990.9

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  • 移植免疫 拒絶反応とT細胞

    鵜殿 平一郎, 中山 睿一

    日本臨床   48 ( 増刊 臨床免疫(下) )   28 - 33   1990.8

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  • 抗CD4及び抗CD8mAbのin vivo投与に対する腫瘍特異的二次反応の抵抗性

    鵜殿 平一郎

    日本免疫学会総会・学術集会記録   19   175 - 175   1989.10

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  • CAPD療法中にIgA型骨髄腫による多発骨折をきたし,肝不全にて死亡した一症例

    安森 亮吉, 鵜殿 平一郎, 迎 寛

    日本透析療法学会雑誌   21 ( 10 )   945 - 950   1988.10

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  • 2次腫瘍拒絶反応の細胞機構

    鵜殿 平一郎

    日本癌学会総会記事   47回   450 - 450   1988.9

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  • 抗クロノタイプモノクローナル抗体によるCTL株10B-5の増殖反応とLyt-2抗体によるその抑制

    鵜殿 平一郎

    日本免疫学会総会・学術集会記録   17   281 - 281   1987.10

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  • 腫瘍特異的拒絶反応の細胞機構

    鵜殿 平一郎

    日本癌学会総会記事   46回   297 - 297   1987.8

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Presentations

  • がん免疫療法実用化の時代~腫瘍微小環境の“3低”を標的にできるか?~

    鵜殿平一郎

    日本がん免疫学会総会プログラム・抄録集  2021 

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  • メトホルミンはROS依存的にNrf2/mTORC1経路を活性化しCD8TILsを賦活する

    西田充香子, 鵜殿平一郎

    日本癌学会学術総会抄録集(Web)  2021 

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  • がん免疫療法における代謝介入

    鵜殿平一郎

    日本癌学会学術総会抄録集(Web)  2021 

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  • 肺腺癌マウスのEP-4阻害剤と抗PD-1抗体の併用療法の解析

    徳増美穂, 西田充香子, 川口高正, 吉田隆雄, 工藤生, 鵜殿平一郎

    日本がん免疫学会総会プログラム・抄録集  2021 

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  • メトホルミンと抗PD-1抗体併用によるCD8T細胞依存性の腫瘍血管正常化

    工藤生, ZHANG Xingda, 西田充香子, 鵜殿平一郎

    日本がん免疫学会総会プログラム・抄録集  2021 

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  • 古くて新しい薬「メトホルミン」〜基礎研究から見えてきた多面的作用〜 メトホルミン誘導性ミトコンドリア活性酸素によるがん免疫再起動

    鵜殿 平一郎, 西田 充香子, 工藤 生

    糖尿病  2020.8  (一社)日本糖尿病学会

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  • メトホルミン誘導性ミトコンドリア活性酸素によるがん免疫再起動

    鵜殿平一郎, 西田充香子, 工藤生

    糖尿病(Web)  2020 

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  • メトホルミンによる糖代謝バランスの改善と腫瘍微小環境の変化に関する組織学的解析

    工藤生, 西田充香子, 鵜殿平一郎

    日本がん免疫学会総会プログラム・抄録集  2020 

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  • ROS依存的なNrf2/mTORC1経路の活性化はメトホルミンと抗PD-1抗体の併用効果を誘導する

    西田充香子, 山下奈穂子, 鵜殿平一郎

    日本がん免疫学会総会プログラム・抄録集  2020 

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  • Egfr改変肺癌マウスモデルを用いたEGFR-TKI,抗VEGFR-2抗体と抗PD-1抗体併用療法の検討

    西井和也, 大橋圭明, 中須賀崇匡, 平生敦子, 大川祥, 渡邉洋美, 狩野裕久, 原尚史, 安東千裕, 二宮貴一朗, 加藤有加, 二宮崇, 久保寿夫, 頼冠名, 市原英基, 堀田勝幸, 田端雅弘, 鵜殿平一郎, 前田嘉信, 木浦勝行

    日本肺癌学会総会号  2020 

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  • 2型糖尿病に対するメトホルミンの抗腫瘍効果

    野島一郎, 榮川伸吾, 梶谷展生, 勅使川原早苗, 宮本聡, 利根淳仁, 内田治仁, 中司敦子, 江口潤, 四方賢一, 鵜殿平一郎, 和田淳

    糖尿病(Web)  2020 

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  • 糖尿尿薬メトホルミンによる腫瘍微小環境の代謝改変と抗腫瘍免疫応答の誘導

    鵜殿平一郎, 西田充香子

    日本分子生物学会年会プログラム・要旨集(Web)  2020 

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  • 肺腺がん細胞のCOX-2欠損はその固形腫瘍形成と増殖を抑制する(COX-2 deficiency in lung adenocarcinoma cells suppresses solid tumor formation and slow down the growth in vivo)

    徳増 美穂, 山崎 千尋, 西田 充香子, 鵜殿 平一郎

    日本癌学会総会記事  2019.9  (一社)日本癌学会

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  • Tumor immunoediting in a lung cancer mouse model harboring EGFR mutations

    Kazuya Nishii, Kadoaki Ohashi, Kiichiro Ninomiya, Go Makimoto, Hiromi Watanabe, Hirohisa Kano, Naofumi Hara, Heiichiro Udono, Katsuyuki Kiura

    CANCER RESEARCH  2019.7  AMER ASSOC CANCER RESEARCH

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  • メトホルミンによる糖代謝バランスの改善と腫瘍微小環境の変化に関する組織学的解析

    工藤生, 西田充香子, 鵜殿平一郎

    日本がん免疫学会総会プログラム・抄録集  2019 

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  • Host immune response in legionella infection

    梶原千晶, 鵜殿平一郎, 石井良和, 舘田一博

    日本細菌学雑誌(Web)  2019 

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  • 遺伝子改変EGFR変異肺癌マウスモデルの腫瘍免疫回避経路の検討

    西井和也, 大橋圭明, 槇本剛, 渡邉洋美, 狩野裕久, 原尚史, 中須賀崇匡, 安東千裕, 二宮貴一朗, 加藤有加, 二宮崇, 久保寿夫, 頼冠名, 市原英基, 堀田勝幸, 田端雅弘, 鵜殿平一郎, 木浦勝行

    日本肺癌学会総会号  2019 

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  • 代謝から読み解く腫瘍免疫研究

    鵜殿平一郎

    日本医学会総会総会会誌  2019 

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  • メトホルミンによる腫瘍微小環境の代謝改変と抗腫瘍免疫応答

    鵜殿平一郎

    糖尿病合併症  2019 

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  • Metabolic reprogramming of tumor microenvironment leads to immune-mediated tumor growth inhibition

    Heiichiro Udono, Mikako Nishida, Shingo Eikawa, Yuuki Kunisada, Takenori Uehara

    CANCER SCIENCE  2018.12  WILEY

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  • 悪性黒色腫に対する抗PD-1抗体による末梢血多機能性CD8陽性T細胞と臨床的有効性の解析

    眞部 恵子, 加持 達弥, 山崎 修, 岩月 啓氏, 榮川 伸吾, 木村 裕司, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集  2018.7  日本がん免疫学会

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    Language:Japanese  

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  • 抗酸化ストレス応答はメトホルミンによる抗腫瘍効果を誘導する

    西田 充香子, 山下 奈穂子, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集  2018.7  日本がん免疫学会

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  • メトホルミンによる腫瘍微小環境の代謝改変と抗腫瘍免疫応答

    鵜殿平一郎

    糖尿病合併症  2018 

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  • ストレスが拓く腫瘍微小環境の代謝改変とがん免疫治療研究への応用

    鵜殿平一郎, 西田充香子

    臨床ストレス応答学会大会抄録集  2018 

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  • 腫瘍微小環境の代謝改変によるがん免疫治療研究

    鵜殿平一郎, 西田充香子

    日本生化学会大会(Web)  2018 

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  • 腫瘍微小環境の代謝改変とがん免疫治療への応用

    鵜殿平一郎, 榮川伸吾, 國定勇希, 西田充香子, 上原健敬

    日本栄養・食糧学会大会講演要旨集  2018 

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  • 2型糖尿病におけるメトホルミンの免疫機能への影響

    野島一郎, 榮川伸吾, 宮本聡, 勅使川原早苗, 利根淳仁, 中司敦子, 江口潤, 四方賢一, 鵜殿平一郎, 和田淳

    糖尿病(Web)  2017 

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  • Mechanisms underlying metformin-mediated enhancement of the protective immune responses against malaria infection.

    MIYAKODA Mana, KIMURA Daisuke, BAYARSAIKHAN Ganchimeg, KIMURA Kazumi, UDONO Heiichiro, YUI Katsuyuki

    日本免疫学会総会・学術集会記録(CD-ROM)  2017 

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  • メトホルミンによるマラリア原虫排除亢進メカニズムの解明

    都田真奈, BAYARSAIKHAN Ganchimeg, 木村大輔, AKBARI Masoud, 木村一美, 鵜殿平一郎, 由井克之

    日本寄生虫学会大会プログラム・抄録集  2017 

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  • 腫瘍微小環境の代謝改変によるがん免疫リブート

    鵜殿平一郎

    日本生化学会大会(Web)  2017 

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  • 腫瘍微小環境における代謝とがんに対する免疫監視 がんの免疫監視機構

    鵜殿平一郎

    がん免疫療法  2017 

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  • 腫瘍微小環境の代謝改変によるがん免疫治療研究

    鵜殿平一郎, 榮川伸吾, 西田充香子

    がんと代謝研究会プログラム&抄録集  2017 

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  • 代謝調節薬を利用したマラリア原虫感染に対する防御免疫機構の解明

    都田真奈, BAYARSAIKHAN Ganchimeg, 木村大輔, AKBARI Masoud, 木村一美, 鵜殿平一郎, 由井克之

    日本寄生虫学会大会プログラム・抄録集  2016 

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  • メトホルミンによるマラリア原虫感染に対する防御免疫亢進機構の解明

    都田真奈, BAYARSAIKHAN Ganchimeg, 木村大輔, AKBARI Masoud, 木村一美, 鵜殿平一郎, 由井克之

    日本インターフェロン・サイトカイン学会学術集会抄録集  2016 

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  • 腫瘍局所のmyeloid-derived suppressor cells(MDSCs)に与えるメトホルミン投与の効果

    上原 健敬, 榮川 伸吾, 國定 勇希, 渡邉 元嗣, 一柳 朋子, 山崎 千尋, 尾崎 敏文, 鵜殿 平一郎

    日本癌学会総会記事  2015.10  (一社)日本癌学会

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  • Modulation of the metabolic status enhances protective immune responses against infection with malaria parasites in γδT cell-dependent manner

    MIYAKODA Mana, BAYARSAIKHAN Ganchimeg, KIMURA Daisuke, AKBARI Masoud, KIMURA Kazumi, UDONO Heiichiro, YUI Katsuyuki

    日本免疫学会総会・学術集会記録  2015 

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    Event date: 2015

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  • メトホルミンは腫瘍浸潤CD8T細胞においてエフェクターメモリー細胞を誘導し、多機能性を付与する(Metformin induced tumor infiltrating CD8 T-cells with effector memory phenotype and multi-functional reversion)

    榮川 伸吾, 根川 真実, 國定 勇希, 上原 健敬, 一柳 朋子, 山崎 千尋, 鵜殿 平一郎

    日本癌学会総会記事  2014.9  (一社)日本癌学会

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    Event date: 2014.9

    Language:English  

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  • 腫瘍局所における免疫疲弊CD8T細胞の機能回復を介したメトホルミンの抗腫瘍効果

    榮川伸吾, 西田充香子, 水上修作, 山崎千尋, 國定勇希, 上原健敬, 有吉勇一, 鵜殿平一郎

    日本がん免疫学会総会プログラム・抄録集  2013 

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    Event date: 2013

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Industrial property rights

  • 免疫疲弊CD8+T細胞の機能改善薬、がん治療薬及びメタボリック症候群の予防または治療薬

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    Application no:特願2013-090431 

    Patent/Registration no:特許6242071号 

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Works

  • 自然界抗癌物質の抗腫瘍効果の解析

    2002
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    2003

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  • 高生理活性のリコンビナント蛋白精製法の確立

    1999
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    2000

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  • ストレス蛋白を用いたワクチン開発

    1998
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    2000

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Awards

Research Projects

  • メトホルミンとファスティング併用による腫瘍微小環境改変に関する研究

    Grant number:21K19409  2021.07 - 2024.03

    日本学術振興会  科学研究費助成事業 挑戦的研究(萌芽)  挑戦的研究(萌芽)

    鵜殿 平一郎

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    Grant amount:\6500000 ( Direct expense: \5000000 、 Indirect expense:\1500000 )

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  • 心血管メカノセンサーTRPV2の低酸素誘発性肺高血圧症への関与解明と治療法開発

    Grant number:21K08108  2021.04 - 2024.03

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    中村 一文, 鵜殿 平一郎, 片野坂 友紀, 赤木 達

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    Grant amount:\4030000 ( Direct expense: \3100000 、 Indirect expense:\930000 )

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  • Metabolism-based dissection of tumor microenvironment infiltrated by immune cells

    Grant number:18H04033  2018.04 - 2023.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (A)  Grant-in-Aid for Scientific Research (A)

    鵜殿 平一郎, 城口 克之, 菱木 貴子, 久保 亜紀子

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    Grant amount:\43810000 ( Direct expense: \33700000 、 Indirect expense:\10110000 )

    腫瘍が退縮する際のCD8TILsとがん細胞の代謝バランス変動と、シグナル分子変動をさらに解析するために以下のように実験を行った。
    A)メトホルミンあるいは抗PD-1抗体との併用における腫瘍免疫応答に際し、Nrf2 コンデイショナルKOマウス及びp62コンデイショナルKOマウスにおけるCD8TILsのmTORC1活性化の有無、オートファジーとの関係、解糖系(Glut-1発現)との関係につき、明らかにした。上記2種類の遺伝子改変マウスでは、CD8TILsにおいてmTORC1活性化の消失(pS6リン低下)、オートファジー機能の消失(LC3B発現低下)、細胞増殖の消失(Ki67発現低下)が認められた。また、Glut-1の発現は、p62KOのCD8TILsにおいてのみ観察された。
    B)腫瘍とそれを取り巻く細胞の代謝・レドックスバランスの解析。In situ 代謝解析を用いた腫瘍微小環境のレドックスおよび代謝状態の解析で本番の実験を行う。マウス腫瘍片、リンパ節、脾臓、肝臓の試料は岡山大学で作成しスライド切片にした後に、研究分担者の久保と菱木(慶應義塾大学)に送付して質量分析解析とイメージングを行った。各種代謝産物(解糖系、TCAサイクル、酸化的リン酸化)およびメトホルミン濃度を測定することができた。
    C)RNAseqによる遺伝子発現解析とそれを基にしたトランスクリプトーム解析を行った。未治療、メトホルミン単独、抗PD-1抗体単独、両者の併用の4群でそれぞれCD8TILsおよび腫瘍細胞をFACSソート回収しそれらの遺伝子発現を RNAseq 法を用いて解析した。その結果、メトホルミンと抗PD-1抗体の併用により生まれる相乗効果のメカニズムについて明らかにすることができた。

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  • Metformin-induced oxidative stress response mediates anti-tumor immunity

    Grant number:17K19598  2017.06 - 2020.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Research (Exploratory)  Grant-in-Aid for Challenging Research (Exploratory)

    Heiichiro Udono

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    Grant amount:\6500000 ( Direct expense: \5000000 、 Indirect expense:\1500000 )

    The underlying mechanism of synergistic effect of metformin (Met), type 2 diabetes drug, and anti-PD-1 Ab, was investigated. Met administration induced ROS-dependent activation of glycolysis of CD8TILs, which connects with activation of both Nrf2 and mTORC1, leading to the enhanced cell proliferation. In Nrf2 conditional KO mice, the effect of Met and the combination therapy was canceled. On the other hand, IFNg production of CD8TILs was solely dependent on glycolysis but not on Nrf2 and mTORC1.

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  • Regulation of function and antitumor effect of regulatory T cells in the tumor microenvironment by metformine, a type 2 diabetes drug

    Grant number:17K15025  2017.04 - 2019.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    Kunisada Yuki, UDONO Heiichiro, EIKAWA Shingo

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    Grant amount:\4420000 ( Direct expense: \3400000 、 Indirect expense:\1020000 )

    We have already demonstrated that the type 2 diabetes drug metformin has antitumor activity via immune cells. In this study, we analyzed the effect of metformin on immunoregulatory regulatory T cells (Tregs), which are said to contribute to tumor growth.
    In the mouse tumor transplantation model, we observed that administration of metformin induced Treg apoptosis and suppressed Treg function in only tumor local sites. In addition, we demonstrated that the metabolism of Treg, which metabolism is dominant in fatty acid oxidation, is predominantly changed from fatty acid oxidation to glycolytic metabolism at the time of differentiation / induction from non-Treg cells to Treg.

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  • Mechanisms of metformin-enhanced gamma delta T cell response during plasmodium infection.

    Grant number:16K08762  2016.04 - 2019.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    MIYAKODA Mana, YUI Katsuyuki, UDONO Heiichiro

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    Grant amount:\4810000 ( Direct expense: \3700000 、 Indirect expense:\1110000 )

    We tried to investigate that the novel effects of metformin, anit-diabetic drug, on the immune responses against plasmodium parasites. Plasmodium infection is one of the severe infections in the world. The immune responses against plasmodium infection are impaired and enough immunological memory is not able to be established. It is important to research the way that enhance immune responses during plasmodium infection. In mouse malaria model, we found that metformin increased the number of gamma delta T cells. Metformin affect neither glycolysis nor mitochondrial respiration in gamma delta T cells although it has been reported that the drug regulates the metabolisms of hepatocytes and skeletal muscle cells. We found that phosphorylation on S6 protein is up-regulated in gamma delta T cells. Therefore, our findings indicated the novel mechanism of metformin on proliferation of gamma delta T cells.

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  • Development of novel immune system analysis and immunotherapy for bone and soft tissue sarcomas

    Grant number:16K15666  2016.04 - 2019.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research  Grant-in-Aid for Challenging Exploratory Research

    OZAKI toshifumi, UEHARA takenori, UDONO heiichiro, FUJIWARA tomohiro

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    Grant amount:\3380000 ( Direct expense: \2600000 、 Indirect expense:\780000 )

    Metformin induces CD11b+-cell-mediated growth inhibition of a K7M2neo osteosarcoma independent of T cells. PMN-MDSCs were significantly reduced in both spleens and tumors following Metformin treatment. In TAMs, production of IL-12 and TNF-α, but not IL-10, became apparent, and elevation of MHC class II with reduction of CD206 was observed, indicating a shift from an M2- to M1-like phenotype via metformin administration. Metformin treatment leads metabolic reprogramming in tumor infiltrated CD11b+ cells. Tumor infiltrated CD11b+ cells were decreased basal respiration and the OCR/ECAR ratio. In addition, uptake of fatty acids was decreased in MDSCs and TAMs, and uptake of glucose was decreased in MDSCs only. Our results suggest that metformin redirects the metabolism of CD11b+ cells to lower oxidative phosphorylation (OXPHOS) while elevating glycolysis, thereby pushing the microenvironment to a state that inhibits the osteosarcoma growth.

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  • Molecular dynamics analysis of IL-17F by infection stage of Legionella pneumonia

    Grant number:26860618  2014.04 - 2018.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    KAJIWARA Chiaki, UDONO Heiichiro

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    Grant amount:\3770000 ( Direct expense: \2900000 、 Indirect expense:\870000 )

    Comparison of survival rates in Legionella infection in wild type mouse, IL-17A deficient mice, IL-17F deficient mice, IL-17AF deficient mice showed a significant survival rate in IL-17AF deficient mice group compared with wild type mouse group Decreased.
    At this time, it was suggested that IL-17F plays an important role in defense against Legionella infection as IL-17A, because IL-17F is overproduced after infection in IL-17A deficient mice. In addition, IL-17F was found to be mainly produced from gamma delta (γδ) T cells which are natural lymphocytes in the acute stage of infection.

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  • Reversion of the exhausted immunity by metformin

    Grant number:26290056  2014.04 - 2017.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

    Udono Heiichiro

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    Grant amount:\16640000 ( Direct expense: \12800000 、 Indirect expense:\3840000 )

    Long term uptake of anti-diabetes drug, metformin, has been shown to reduce cancer incidence and mortality. However, the underlying mechanism of this effect is not yet understood. Immune system against cancers, particularly, CD8T cells (killer cells) undergoes exhaustion in tumors, which allows for tumor growth. We found that metformin reactivates exhausted CD8T cells in tumors to fight against cancer cells through elevation of their glycolysis, leading to the retardation of tumor growth.

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  • Reversion of exhausted T cells in tumor microenvironment

    Grant number:26670237  2014.04 - 2016.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research  Grant-in-Aid for Challenging Exploratory Research

    Udono Heiichiro

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    Grant amount:\3770000 ( Direct expense: \2900000 、 Indirect expense:\870000 )

    Elevation of glycolysis in CD8 tumor infiltration lymphocyte (CD8TIL) was found by metformin (Met) administration. Also, mature CD8T cells differentiated from naive CD8T cells by in vitro TCR stimulation revealed enhanced glycolysis as well as oxidative phosphorylation by Met-treatment. Intestinal micro flora was not altered by Met. Significant reduction of Treg in tumors was also observed by Met. Inducible Treg (iTreg) differentiated from naive CD4T cells by TCR stimulation and TGFbeta was reduced in number and suppressive function by Met-treatment. Furthermore, reduction of MDSC in number, especially, G-MDSC rather than M-MDSC, was prominent in tumor tissue by Met. Also, increase of M1/M2 macrophage ration was observed by Met. It is clear that Met-administration dramatically changes tumor microenvironment towards favorable state for anti-tumor immunity.

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  • Analysis of a role of Hsp90α in antigen cross presentation

    Grant number:22501027  2010 - 2012

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    UDONO Heiichiro

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    Grant amount:\4420000 ( Direct expense: \3400000 、 Indirect expense:\1020000 )

    Analysis of a role of Hsp90α in antigen cross presentation In antigen cross-presentation, dendritic cells (DCs) take up extracellular antigens (Ag) and translocate them from the endosome to the cytosol for proteasomal degradation. The molecules responsible for Ag translocation are unknown. By using Hsp90α KO mice, we demonstrated that HSP90 is essential in pulling endosomal Ag out into the cytosol.

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  • シヤペロンによる再構築されたプロテアソームの構造機能解析

    Grant number:17659143  2005 - 2006

    日本学術振興会  科学研究費助成事業 萌芽研究  萌芽研究

    鵜殿 平一郎

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    Grant amount:\3300000 ( Direct expense: \3300000 )

    分子シャペロンhsp90αを用いて、任意の細胞抽出液より26Sプロテアソームをin vitro構築することが可能である事を明らかにし、その構造及び機能の解析を行った。その結果以下の事が明らかになった。
    1、ヒスチジンタグ-hsp90αをATP存在下の細胞抽出液に加えイミダゾールで回収する事により、26Sプロテアソーム及びハイブリッドプロテアソームが得られた。これらのプロテアソームは特異的基質であるsuc-LLVY-amcを加水分解した。またこの分子複合体は、hsp90の特異的阻害剤であるゲルダナマイシン処理により構造が破壊された。即ち、これらのプロテアソームの構築とその維持にhsp90αが重要な役割を果たしていることが推察された。
    2、ヒスチジンタグ-hsp90αをATP非存在下の細胞抽出液に加える事により、hsp90α-20Sプロテアソームを構築する事ができた。このプロテアソーム複合体は、特異的基質であるsuc-LLVY-amcに対する加水分解活性を示さないが、MHCクラスIペプチドをフランキングを含む合成ペプチドから切り出す事ができた。また、この分子複合体の中には、hsc70,hsp40,p23,CHIPなどのシャペロン或はコシャペロン分子が会合していた。この分子複合体をさらにATP処理するとhsp40,p23,CHIPは遊離し最後にhsp90α/hsc70/20Sのみからなる複合体が得られた。hsp90α/hsc70/20Sは同様に合成ペプチドを切断する事ができた。一方、シャペロンの会合しない20Sのみの構造ではMHCクラスIペプチドを切り出す事は出来なかった。この結果は新規のプロテアソームの存在を示唆するが、生理学的にそのような構造のプロテアソームが細胞内に存在するか否かについてはさらなる検討が必要と考えられた。

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  • ヒト癌組織における抗原ペプチド産生能に関する基礎的研究

    Grant number:17016081  2005

    日本学術振興会  科学研究費助成事業 特定領域研究  特定領域研究

    鵜殿 平一郎

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    Grant amount:\7800000 ( Direct expense: \7800000 )

    微量のヒト癌組織からオーダーメイドにプロテアソームを分離精製する事を可能にした。
    1,リコンビナント-ヒトhsp90α、の発現・精製を行った。
    2,2例のヒト癌組織からのライセートの調整およびプロテアソームのin vitroアッセンブリ;大腸癌及び周囲の正常組織約0.1〜0.6cm^3から細胞ライセートを作製し、hsp90αを加えて、プロテアソームのアッセンブリを行った。
    3,アッセンブリされたプロテアソームの精製系の確立;1、におけるリコンビナント蛋白は全て6xヒスチジンタグをそのN末側にもつ。Ni^<2+>アガロースでpull downし、これをnative-PAGEで分離しsuc-LLVY-amc及びboc-LRR-amcの加水分解活性を指標に活性を検出した(In-Gel hydrolysis assay)。
    4,native-PAGEゲルをニトロセルロース膜に転写し、特異的抗体を用いてプロテアソームの構造解析を行った。
    結果)0.1cm^3ほどのヒト癌組織又はその周囲の正常組織より酵素活性を有したプロテアソームを再構成し、分離精製できた。得られたプロテアソームはハイブリッド型とホモPA28型が主体であり、キモトリプシン様活性を有していた。しかし、トリプシン様活性は正常組織より回収したホモPA28型プロテアソームで極めて高いのに対し、癌からの活性は微弱であった。また、品質管理E3ユビキチンリガーゼと呼ばれるCHIPが両方の組織のホモPA28型プロテアソームに会合していた。20Sコアについては、正常組織ではXタイプ優位のスタンダード型が、癌組織では免疫プロテアソームのタイプが優位であった。以上より極微量(〜0.1cm^3)の凍結癌組織からhsp90αを用いてプロテアソーム再構成を促し、精製分離できることが明らかにされた。これらのプロテアソームを用いて癌ペプチド前駆体の切断実験が可能と判断された。

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  • Enhancement of anti cancer immunity by fusion protein of HSP70 and CD8 T cell epitope from NY-ESO-1

    Grant number:16591263  2004 - 2005

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    NAGATA Yasuhiro, UDONO Heiichiro, KANEMATSU Takashi

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    Grant amount:\3400000 ( Direct expense: \3400000 )

    Heat shock proteins(HSPs) 70 are a family of highly conserved molecules with ATPase activity and relative molecular masses around 70,000 kDa. Hsp proteins chaperone antigenic peptides into antigen-presenting cells, potentially allowing peptides to enter the MHC class I pathway for loading onto MHC class I molecules, where they can be presented to cytotoxic CD8+ T cells. In turn, this provides a strategy for immunization against cancer by using hsp and bound peptides that are isolated from tumors. Immunization with heat shock cognate protein 70 (hsc70) bound to synthetic peptides by in vitro reconstitution has been shown to induce peptide-specific CTL in mice. Here, we succeed genetically to fuse hsc70 and a CTL epitope derived from NY-ESO-1, one of the cancer-testis antigens. We also have shown dendritic cell can present the epitope onto their MHC class I after feeding the fusion protein. Hsc70 with NY-ESO-1 peptide can be processed through cytosolic pathway and presented by DCs to CD8^+ T cell clones. These findings help devising and validating vaccine strategies with Hsc-NY-ESO-1 epitope fusion protein.

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  • 癌免疫におけるプロテアソーム活性化分子群の研究

    Grant number:16023250  2004

    日本学術振興会  科学研究費助成事業 特定領域研究  特定領域研究

    鵜殿 平一郎

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    Grant amount:\5900000 ( Direct expense: \5900000 )

    MHCクラスI抗原プロセシングにおける、PA28,hsp90,hsp70の機能を解析した。まず、PA28 hsp90,hsp70とプロテアソームがどのような関係にあるのかを構造解析を通して検討した。Hsp90,hsp70はプロテアソームと複合体を形成しうるが、その際のATP濃度がどちらのシャペロンが結合するかを決定しているらしい事実を見つけた。また、PA28はATP濃度が低いときにはフットボール型プロテアソーム或はhsp70結合型ハイブリッドプロテアソームとして存在するが、ATP濃度が高いときにはhsp90結合型ハイブリッドプロテアソームとして存在しうるらしい事を明らかにした。即ちプロテアソーム複合体の存在様式は同一細胞内であっても非常に動的である。また、リコンビナントhsp90及びPA28αによりプロテアソーム複合体を細胞ライセートからプルダウンすることに成功した。ATP存在下でHsp90によりプルダウンされるプロテアソームは26Sタイプとハイブリッドプロテアソームであり、一方、PA28αによるプロテアソームではATP非存在下ではフットボール型が主であり、ATP存在下ではハイブリッドプロテアソームが得られる。これらの複合体のSuc-LLVY-amc加水分解活性を確認後、合成ペプチドTRP2180-193(TRP2180-188がエピトープ),CSP277-294(CSP281-289がエピトープ)とインキュベーションし、ペプチドの切断実験を行った。その結果、TRP2180-188産生にはPA28が必須であり、CSP281-289の産生にはhsp90が必須であった。これは、我々が以前にin vivoの実験で明らかにしてきた現象の分子機構を説明したものと解釈できる。

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  • The analysis of cell lineage specific expression of perforin gene

    Grant number:15591013  2003 - 2004

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    MIYAZAKI Yasushi, UDONO Heiichiro

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    Grant amount:\2300000 ( Direct expense: \2300000 )

    MEF is a member of Elf-sub family of ETS transcription factors. MEF was shown to activate the expression of GN-CSF and IL-3 genes, which Elf-1, the closest gene to MEF, also transactivates. However, gene knock-out experiments demonstrated that MEF is indispensable for the expression of perforin gene in NK cells but not in suppressor T-cells, on the other hand, Elf-1 knock-out mice did not show clear phenotype. To elucidate the mechanisms of lineage specific expression of perforin gene, we planned two things : (1)determine the protein(s) that associate with MEF and (2)compare it with those of Elf-1. For this purpose, we performed "tandem affinity purification"(TAP) analysis using MEF as bait Cells trasfected with the expression plasmid for MEF were lysed and purified twice with Ig G cepharose beads and calmodulin regine, then associated proteins with MEW were fractionated by SDS-PGE. After visualized with protein staining, each bands was analysed with LC-MAS spectrometry. Proteins picked up were : Myb binding protein, nucleolin, RNA helicase, vimentin, nucleophosmin. Among those, nucleophosmin was shown to be mutated in one-third of acute myeloid leukemia recently, suggesting its important roles in hematopoietic cells. We are now in the process of the analysis for the direct physical and functional interactions between MEF and nucleophosmin.

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  • MHC多様性と抗原提示における分子シャペロンの機能解析に基づく癌免疫治療研究

    Grant number:15025259  2003

    日本学術振興会  科学研究費助成事業 特定領域研究  特定領域研究

    鵜殿 平一郎

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    Grant amount:\5900000 ( Direct expense: \5900000 )

    細胞内シャペロン分子、とりわけストレス蛋白Hsp90、hsp70、hsp40の内在性抗原プロセッシングにおける機能について解析を行った。また、プロテアソーム活性化分子PA28α分子の機能もそのドミナントーネガテイブ分子を用いて解析を行った。同研究は現在も進行中であるが、期問内に明らかになった事項を下に列記する。
    1、Hsp90はPA28分子と同様、MHCクラスI抗原ペプチドのCOOH末flanking部位を、20Sプロテアソームを活性化することにより促進している。
    2、Hsp70はhsp40の存在下に20Sプロテアソームを活性化し、hsp90と同様にMHCクラスII抗原ペプチドのプロセッシングに関与することが明らかになった。
    3、PA28分子は、多くの場合MHCクラスI抗原ペプチドのプロセッシングを促進するが、マウスではK^d, D^d結合性ペプチドの産生にはむしろネガテイブに作用することが明らかになった。これはヒト、特に日本人に多いHLA-A2結合性ペプチドにも当てはまると考えられる。この理由は、これらのMHCクラスI分子結合ペプチドのアンカーアミノ酸の存在により、ペプチドが20Sプロテアソームによりエピトープ内で切断されやすくなるためと推測された。一方hsp90による抗原ペプチドのプロセッシングはMHCアレルとの相関関係は認められなかった。
    4、Hsp90,hsp70/hsp40が20Sプロテアソームを直接活性化できるのかどうかが今後in vitroの実験系で確認しなければならない事項と考えられる。

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  • 抗原プロセッシングにおけるhsp90、PA28の機能解析

    Grant number:14657058  2002 - 2003

    日本学術振興会  科学研究費助成事業 萌芽研究  萌芽研究

    鵜殿 平一郎, 由井 克之

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    Grant amount:\3300000 ( Direct expense: \3300000 )

    細胞内シャペロン分子、とりわけストレス蛋白Hsp90、hsp70、hsp40の内在性抗原プロセッシングにおける機能について解析を行った。また、プロテアソーム活性化分子PA28α分子の機能もそのドミナントーネガテイブ分子を用いて解析を行った。同研究は現在も進行中であるが、期間内に明らかになった事項を下に列記する。
    1、Hsp90はPA28分子と同様、MHCクラスI抗原ペプチドのC00H末flanking部位を、20Sプロテアソームを活性化することにより促進している。
    2、Hsp70はhsp40の存在下に20Sプロテアソームを活性化し、hsp90と同様にMHCクラスI抗原ペプチドのプロセッシングに関与することが明らかになった。また、Hsp40ドミナントーネガテイブ分子は内在性抗原プロセッシングを抑制する。
    3、PA28分子は、多くの場合MHCクラスI抗原ペプチドのプロセッシングを促進するが、マウスではK^d,D^d結合性ペプチドの産生にはむしろネガテイブに作用することが明らかになった。これはヒト、特に日本人に多いHLA-A2結合性ペプチドにも当てはまると考えられる。一方hsp90による抗原ペプチドのプロセッシングはMHCアレルとの相関関係は認められなかった。
    4、Hsp90,hsp70/hsp40が20Sプロテアソームを直接活性化できるのかどうかが今後in vitroの実験系で確認しなければならない事項と考えられる。

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  • Application of Heat-shock protein with antigenic peptide for cancer vaccine

    Grant number:14571146  2002 - 2003

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    NAGATA Yasuhiro, KANEMATSU Takashi, UDONO Heiichiro

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    Grant amount:\3500000 ( Direct expense: \3500000 )

    Heat shock proteins(HSPs) 70 are a family of highly conserved molecules with ATPase activity and relative molecular masses around 70,000 kDa. Hsp proteins chaperone antigenic peptides into antigen-presenting cells, potentially allowing peptides to enter the MHC class I pathway for loading onto MHC class I molecules, where they can be presented to cytotoxic CD8+ T cells. In turn, this. provides a strategy for immunization against cancer by using hsp and bound peptides that are isolated from tumors. Immunization with heat shock cognate protein 70 (hsc70) bound to synthetic peptides by in vitro reconstitution has been shown to induce peptide-specific CTL in mice. Here, we succeed genetically to fuse hsc70 and a. CTL epitope derived from NY ESO-I, one of the cancer-testis antigens. We also have shown dendritic cell can present, the epitope onto their MHC class I after feeding the fusion protein. Hsc70 with NY ESO-1 peptide can be processed through cytosolic pathway and presented by DCs to CD8^+ T cell clones. These findings help devising and validating vaccine strategies with Hsc-NY ESO-l epitope fusion protein.

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  • ストレス蛋白hsp90,PA28の分子生物学的特性に基づく癌免疫治療研究

    Grant number:14030067  2002

    日本学術振興会  科学研究費助成事業 特定領域研究  特定領域研究

    鵜殿 平一郎, 由井 克之

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    Grant amount:\5500000 ( Direct expense: \5500000 )

    プロテアソーム調節分子PA28は20Sプロテアソームのペプチド分解活性を促進し、癌抗原を初めとする多くの抗原ペプチドのプロセシングを促進すると考えられている。一方、相当数の抗原ペプチドのプロセシングはPA28により促進されないことも報告されている。我々の研究結果はさらに踏み込み、MHCクラスI結合ペプチドのアンカーモチーフ構造がPA28依存性のプロセシングに影響を与える可能性を示唆した。さらには、hsp90がPA28に類似の機能を有することを明らかにし、MHCクラスI抗原のプロセシングがPA28とhsp90のそれぞれ異なる経路に支配されていることが明らかになった。即ち、抗原ペプチドはPA28-、hsp90-、或いはこの両者によってプロセシングされるものに分類され、その大原則にペプチドのアンカーモチーフが関与している。
    またPA28α鎖のドミナント-ネガティブ分子(PA28αΔC5)を発見した。PA28αΔC5を含むハイブリッドプロテアソームの酵素活性は完全に消失する。本来PA28-プロテアソーム分子は蛋白分解の酵素であり、抗原提示専門の酵素ではないため、非常にバラエティに富む働きを行っていると考えるのが当然であり、事実、細胞周期及びアポトーシスの制御に関与があることがPA28αΔC5を用いた実験で初めて明らかになった。これらの原因は即ちPA28-プロテアソーム分子により、ある程度選択的に細胞周期関連分子の分解が行われているためであり、その結果アポトーシス制御にも影響を及ぼすということである。
    以上の結果は、抗原提示のみならず、癌細胞の増殖、死滅においてもPA28分子が非常に重要な機能を果たす可能性を示唆しており、今後PA28の機能をうまくコントロールすることにより癌治療に大いに貢献できる可能性があると考えられる。

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  • Molecular mechanisms To protect malaria infection by vaccine using antigen / hsp70 fusion protein

    Grant number:13670248  2001 - 2002

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    HONMA Kiri, UDONO Heiichiro, YUI Katsuyuki

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    Grant amount:\3600000 ( Direct expense: \3600000 )

    APCs can internalize some types of exogenous antigens for processing and presentation on MHC class I molecules, which is referred to as cross-presentation. It is known that peptides associated with hsp70 can be presented in this manner to induce specific CTLs. To determine the cross-presentation pathway of hsp70 associated peptides, we generated hsc70-OVA_<257-264> (hsc70-OVA) fusion protein, which could induce specific CTL in vivo. CD8^+ T cells (OT-1 cells) were isolated from K_b-restricted OVA_<257-264> specific TCR transgenic mice (OT-1). RMA, RMA-S (TAP-) or bone-marrow derived DC, which were generated from C57BL/6 or TAP KO mice, were used as ARC. To determine whether APC can cross-present hsc70-OVA, we measured IFN-γ production from OT-1 cells in response to hsc70-OVA-pulsed ARC, and the expression of K_b-OVA_<257-264> complex on APC using 25D1.16 mAb. Our results showed that, 1) OT-1 cells produced IFN-γ in response to hsc70-OVA-pulsed TAP-negative 8M-DC, 2) High levels of K_b-OVA_<257-264> complex were detected on hsc70-OVA-pulsed RMA. The levels of K_b-OVA_<257-264> complexes detected on hsc70-OVA-pulsed RMA-S were similar to RMA. 3) The expression level of K_b-OVA_<257-264> complexes on RMA was only partially Inhibited by brefeldin A. 4) The expression of K_b-OVA_<257-264> complexes on RMA was completely inhibited by pretreatment of pCMBS, which is the inhibitor of fluid phase endocytosis (macropinocytosis). However, IFN-γ production from OT-1 T cells were not inhibited when BM-DC were treated with pCMBS. 5) IFN-γ production from OT-1 T cells were reduced when BM-DC were pulsed with hsc70-OVA in the presence of hsc70. Our results suggest that there are two distinct pathways of endocytosis of hsc, macropinocytosis and receptor-mediated endocytosis, and that there existed TAP-independent cross-presentation pathway of hsc associated peptide.

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  • ストレス蛋白の分子生物学的特性に基づく癌免疫治療研究

    Grant number:13218102  2001

    日本学術振興会  科学研究費助成事業 特定領域研究(C)  特定領域研究(C)

    鵜殿 平一郎, 由井 克之

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    Grant amount:\5200000 ( Direct expense: \5200000 )

    リコンビナントhsc70-癌抗原ペプチド融合分子により活性の高いCTLを誘導できることを我々は明らかにした。一方CTL認識ペプチドをIFAと混合して免疫する際に同じMHCハプロタイプ(クラスII)拘束性のヘルパーペプチドと同時投与してやるとCTLの感作が強く行われる。そこで、hsc70分子のN末にモデル抗原OVA(ovalubumin)のI-A^b拘束性ペプチドOVA_<265-280>を融合し、同時にC末にCTLエピトープOVA_<257-264>を融合させたリコンビナント分子を作製した。この分子でマウスを免疫し脾臓細胞をin vitroで6日間ペプチド刺激し、得られたエフェクター細胞(CD8^+T細胞)の細胞傷害活性とELISPOTアッセイ法によるIFNγ産生細胞数を解析した。その結果細胞傷害活性はCTLエピトープ単独融合分子とヘルパー及びCTLエピトープ両方融合分子では差が認められなかった。しかし、IFNγ産生細胞数はヘルパーエピトープ付加により、2〜4倍に増加した。即ち、ヘルパーエピトープはhsc70に融合した場合、CD8^+T細胞の感作活性を増強させることが判明した。OVA_<265-280>の代わりにI-A^d拘束性のPlasmosium yoelii circumsporozoite蛋白由来のヘルパーエピトープを融合させた場合にはOVA_<257-264>に対する反応性の亢進は認められないことよりMHC拘束性が確認された。さらにOVA_<265-280>とマウスメラノーマ抗原TRP2_<180-188>の両方をhsc70に融合し、同様に解析した結果、TRP2_<180-188>に対してIFNγ産生細胞数はTRP2_<180-188>単独融合分子の場合よりもやはり2〜4倍増加していた。即ち、ヘテロのヘルパーエピトープであってもMHC拘束性が一致していれば感作されるCD8^+T細胞数が増加することが判明した。

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  • Induction of protective immunity against malaria by MSP1/hsc70 fusion protein vaccine

    Grant number:12670234  2000 - 2001

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    YUI Katsuyuki, UDONO Heiichiro

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    Grant amount:\3900000 ( Direct expense: \3900000 )

    We have developed a method to induce CD4 and CDS specific immune responses by immunizing mice with a particular antigen as a fusion partner of mouse heat-shock cognate protein 70 (hsc70). We used this strategy to induce protective immunity against malaria sporozoite infection. We generated a recombinant protein of MSP1 fused to hsc70 (MSP1/hsc70) and studied whether it could induce protective immunity against liver stage P. yoelii, since we found that MSP1 is expressed during liver stage of P. yoelii life cycle. The immunization of mice with MSP1/hsc70 without any additional adjuvant induced strong specific antibody responses and IFN-y production. When the immunized mice were challenged with P. yoelii sporozoites, the onset of parasitemia delayed a few days when compared with naive mice or mice immunized with hsc70 alone, suggesting the induction of protective immune responses against liver stage malaria. To confirm the MSP1-specific protective immune responses against exoerythrocytic forms of malaria infection, we performed RT-PCR analysis of P. yoelii-specific rRNA in the infected liver. The level of P. yoelii was reduced in mice immunized with this fusion protein, but not in mice immunized with hsc70 alone, suggesting that MSP1-specific protective immunity is effective at liver stage malaria. This protective immunity was transferred into naive mice by spleen cells or liver lymphocytes of immune mice but not by antiserum, indicating that the protection is mediated by cellular mechanisms. Finally, the vaccine-induced protection was observed in C57BL/6, A/J, BALB/c and C3H mice suggesting that MSP1-specific protective immunity at the exoerythrocytic stage can be induced in animals over a wide range of genetic backgrounds.

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  • ストレス蛋白-癌抗原融合分子による抗腫瘍効果

    Grant number:12217113  2000

    日本学術振興会  科学研究費助成事業 特定領域研究(C)  特定領域研究(C)

    鵜殿 平一郎, 新原 直樹, 由井 克之

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    Grant amount:\5100000 ( Direct expense: \5100000 )

    我々はCTL認識抗原ペプチドを遺伝子工学的にストレス蛋白分子hsc70と融合させた融合分子がワクチンとして確実な効果があることを証明し、その細胞性免疫誘導機構及びストレス蛋白分子のどのような性状にそれが依拠するのかを明らかにした。腫瘍抗原ペプチドpRL1a(マウス白血病細胞RL♂1のLd拘束性ペプチド)、TRP2(マウスメラノーマB16のKb拘束性ペプチド)、さらにモデル抗原としてOVA257-264をそれぞれhsc70のC末に融合してその免疫効果を検討した。これら3つのペプチドに対して強力なCTLが誘導された。これらのCTLはオリジナルの腫瘍に対しても高い傷害活性を示した。CTLエピトープの融合部位はhsc70のN末、C末どちらでもよかった。in vivoへの投与経路は皮下、皮内ではなく静脈内投与が最も効果的であった。このことはhsc70のターゲットとする抗原提示細胞は皮下ランゲルハンス細胞ではないことを意味している。むしろ、脾臓内未熟樹状細胞、或いはマクロファージの可能性が高い。hsc70融合分子によるCTL誘導にはCD4^+T細胞は必須ではなかった。また、免疫の際にカラゲナンを投与するとhsc70融合分子によるCTL誘導は全く消失するためカラゲナン感受性の抗原提示細胞がhsc70融合分子のプロセッシングにあたると推測された。
    次にhsc70のどの領域がCTL誘導に必須であるかを検討するためにhsc70のdeletion mutantsとCTIエピトープの融合分子を作製した。その結果hsc70280-385の間に必須領域があると判断した。
    hsc70はある細胞表面受容体をもつ特定の抗原提示細胞に特異的に取り込まれると考えられている。この受容体の特定と同時にhsc70280-385と受容体の結合を介して細胞内に取り込まれる可能性を今後検討する。

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  • Molecular mechanism of vaccination effect induced by stress protein-Malaria CS antigen

    Grant number:11670245  1999 - 2000

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    UDONO Heiichiro, YUI Katsuyuki

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    Grant amount:\3500000 ( Direct expense: \3500000 )

    Immunization with gp96 and hsc70 that bound naturally occurring peptides in vivo or bound synthetic peptides by in vitro reconstitution, have been shown to induce peptide specific CTLs. In addition, mycobacterial hsp70 covalently fused to OVA-derived fragments was shown to generate MHC class I restricted CL responses. In the present study, five different CTL epitopes, including peptides derived from Plasmodium yoelii circumsporozoite protein, tumor antigens, HY antigen and OVA, were genetically fused either to N or C terminus of murine heat shock cognate protein 70 (hsc70), and expressed in E.coli. Peptide specific CTLs were induced by vaccination with all the fusion proteins, indicating that no cognate flanking regions of CTL epitopes are necessary. A root of injection was crucial for CIL induction. CD4^+ T cells were not required for the priming of CD8^+ T cells, and vaccination with bone-marrow derived dendritic cells pulsed with fusion proteins also elicited CL responses. Furthermore, by using deletion mutants of hsc70, the most responsible region of hsc70 to generate CTLs was mapped to hsc70_<280-385>.

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  • 不活化スポロゾイトの免疫による赤内型マラリア原虫に対する防御免疫誘導機構

    Grant number:11147226  1999

    日本学術振興会  科学研究費助成事業 特定領域研究(A)  特定領域研究(A)

    由井 克之, 鵜殿 平一郎

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    Grant amount:\1700000 ( Direct expense: \1700000 )

    X線照射により不活化したPlasmodium yoelii(P.yoelii)スポロゾイトで繰り返しマウスを免疫することにより、抗マラリア原虫抗血清を作成した。この抗血清を用い、Western blot法で赤内型原虫抗原を解析することにより、複数の抗原を同定した。主要なものは、P.yoelii HSP70、MSP1抗原及び未同定の抗原であった。これらの抗原は、肝細胞期と赤血球期原虫の両者に発現されると考えられる。赤内型P.yoelii のcDNAライブラリーを作成し、P.falciparum HSP70のプローブでスクリーニングすることにより、P.yoelii HSP70のcDNAをクローニングした。また抗血清で同ライブラリーをスクリーニングすることにより、新たなマラリア原虫抗原cDNAをクローニングした。この新抗原cDNAの全塩基配列はまだ決定されていないが、従来同定されていない新しい原虫抗原であることが明らかになっている。
    MSP1が赤内型と肝細胞期両者に発現されることから、MSP1抗原C末端のEGF様ドメインを含む15kDaペプチド断片とマウスHSP70との組換え融合分子を作成した。他のアジュバントなしでこの融合蛋白で免疫することにより、肝細胞期と赤血球期両者に有効な防御免疫を誘導することに成功した。C57BL/6マウスではスポロゾイト感染後赤内型原虫が全く出現せず、肝細胞期における感染阻止が示された。この防御免疫能は、血中抗MSP1抗体価とは直接の相関がなかった。一方、免疫マウスは赤内型原虫の感染に対しても抵抗性を示した。このことから、MSP1/HSP70融合蛋白ワクチンの免疫により肝細胞型と赤内型両者に有効な防御免疫が誘導されると考えられた。

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  • ストレス蛋白・癌抗原融合蛋白分子による抗腫瘍効果

    Grant number:11140257  1999

    日本学術振興会  科学研究費助成事業 特定領域研究(A)  特定領域研究(A)

    鵜殿 平一郎, 由井 克之

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    Grant amount:\2700000 ( Direct expense: \2700000 )

    マウスのhsc70遺伝子を鋳型として3'側のプライマーに癌抗原ペプチドpRL1a(RL♂1)、TRP2(B16)、又はマラリアCS抗原、OVA抗原(E.G7)、HY抗原をコードするmini-geneをそれぞれ入れ、PCR法で遺伝子増幅する。これを発現ベクターに組み込み大腸菌にて大量に発現された。それぞれの蛋白分子1mgで隔週2回免疫し、脾臓細胞を取り出し同ペプチドでin vitro刺激を行いELISPOT法とクロム51遊離試験で効果を比較した。いずれの抗原ペプチドでも特異的な細胞傷害性T細胞(CTL)の誘導が可能であることが判明した。即ち、抗原ペプチドの種類に制限はないと考えられた。さらにRL♂1、B16、E.G7を皮内に注射しvivoで腫瘍増殖の抑制効果を判定する試みを現在も続けているが、完全抑制とまではいかないようである。しかし、マラリア抗原MSP-1のほぼ全長とhscp70の融合分子はスポロゾイト攻撃感染を肝臓期に完全に抑制するという実験結果も我々は得ており、このことから単一のCTLエピトープだけではなくヘルパーエピトープも含めた複数のエピトープがより強力なワクチン効果を発揮する上で重要であると推察された。
    通常、リコンビナントhsc70分子にはほとんどATPase活性が認められないのが現実であるが、我々の特種なrefolding操作によりnative分子と同様のATPase活性を持ったhsc70蛋白分子の精製を可能にした。このATPase活性の強さとCTL感作の強さに相互関係があることがわかった。また、hsc70のN末側アミノ酸280番から300番目の間にCTL感作に大きく影響を及ぼす領域があることが変異hsc70分子を用いた実験で明らかになった。

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  • 熱ショック蛋白と免疫応答

    1998

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    Grant type:Competitive

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  • HSP 70 of Cryptococcus neoformans in Cryptococcosis.

    Grant number:08670667  1996 - 1998

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    KOHNO Shigeru, UDONO Heiichiro

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    Grant amount:\2200000 ( Direct expense: \2200000 )

    Cryptococcus neoformans causes infection in individuals with defective T-cell function, such as AIDS, as well as without underlying disease. It has been suggested that humoral as well as cellular immunity might play an important role in the immune response to C.neoformans infection. We have recently shown, using immunoblotting, that the 70-kDa heat shock protein (HSP) family of C.neoformans was the major target molecule of the humoral response in murine pulmonary cryptococcosis. In this study, we also used immunoblotting to define the antibody responses in the sera of 24 patients with pulmonary cryptococcosis - 21 proven and 3 suspected diagnoses. Anti-C.neoforinans HSP 70 antibody was detected in 16 of 24 (66.7%) patients with pulmonary cryptococcosis. Fourteen of 17 (82.3%) patients with high antigen titers (*1 : 8) and 2 of 7 (28.6%) patients with low titers (*1 : 4), had detectable levels of anti-HSP 70 antibody. Sera from patients positive for anti-HSP 70 antibody showed high titers in the Eiken latex agglutination test for the detection of serum cryptococcal antigen. Our results indicate that the 70-kDa heat shock protein family from C.neoforinans appears to be a major target molecule of the humoral response, not only in murine pulmonary cryptococcosis, but also in human patients with pulmonary cryptococcosis.

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  • 熱ショック蛋白結合性腫瘍抗原ペプチドの解析

    Grant number:07274244  1995

    日本学術振興会  科学研究費助成事業 重点領域研究  重点領域研究

    鵜殿 平一郎

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    Grant amount:\3100000 ( Direct expense: \3100000 )

    Meth A腫瘍由来のHSPの分離、精製を一部改良し非常に高純度のHSPを精製し結合している内因性ペプチドの同定、解析を改めて行った。Meth A腫瘍の10万gの上清を硫安沈殿法にて0-50%、50-80%の分画に分けた。50-80%の画分にはgp96が存在しておりこれをさらにCon A sepharose及びMono Qカラムを用いたFPLCにて高純度(98%以上)のgp96を精製し。また、Con A sepharoseに結合しない分子及び硫安沈殿法にて0-50%の画分蛋白を混合しMono Qカラムを用いてcrudeのhsp70を精製しさらにADPアガロースカラムを用いて98%以上の純度でhsp70を精製することに成功した。このhsp70にはMeth Aに対する抗腫瘍効果が認められた。同hsp70をATP処理し、遊離してきた低分子をC18逆相カラムにてHPLC解析を行いペプチドの存在を確認した。これらペプチドのプールシークエンスを行った結果は作年我々が指摘したものと同じようにN末1番目のアミノ酸はIIe,Leu,Valの分岐鎖アミノ酸、及びAla,Pheの頻度が高く合計すると全体の70%くらいを占める。2番目にはこれらのアミノ酸残基に加えAsn,Asp,Glu,Gln,Lys,Ser,Thrなどの親水性のアミノ酸が位置していた。Gly,Proは3番目から7番目くらいに高頻度に認められた。Gp96からTFA処理にて得られたペプチドのプールシークエンスも同様の結果であった。さらに現在gp96及びhsp70から遊離してきた一部のペプチドピークをエドマン分解法にてそのアミノ酸配列を決定している。

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  • Investigation of Vaccination Effect by Hsp 70-Malaria Antigen Peptide Complex

    Grant number:06670259  1994 - 1995

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for General Scientific Research (C)  Grant-in-Aid for General Scientific Research (C)

    UDONO Heiichiro, ONO Toshiro

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    For establishment of preerythrocytic vaccination model against mice malaria Plasmodium berghei, we tried to induce cellular immunity to CS protein of plasmodium berghei.
    1.Cytotoxic T cell epitope, NDDSYIPSAEKI which is recognized in a context with H-2 K^d by CTL lines against CS protein of Plasmodium berghei was biochemically synthesized. This 12mer peptide and heat shock protein 70 were mixed and incubated for 1 hour ar 37゚C for making the hsp70-peptide.
    2.BALB/c mice were immunized with 10mg (per mouse) of this hsp70-peptide complex twice at a week interval and spleens were removed and suspended cells were incubated with the peptide for five days in 5% CO_2,37゚C.Cytotoxic activity of the effector cells was assayd with ^<51>Cr labelled P815 target cells pulsed with the peptide.
    3.By in vitro stimulation with the different dose, 1 x 10^<-4>,1 x 10^<-5>,1 x 10^<-6>,1 x 10^<-7>,1 x 10^<-8> mol of the peptide, optimal concentrations of the peptide were identified as 1 x 10^<-6> and 1 x 10^<-7> mol for induction of primary CTLs.
    4.Incubation of spleen cells with the peptide in the presence of IL2 revealed no mounting effect of cytotoxic activity was observed, rather IL2 decreased the activity.
    5.Since repeated stimulation of effector cells with the peptide apparently increased the cytolytic activity, establishment of long term cultured cell lines were on going now.

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  • 熱ショック蛋白結合性腫瘍抗原ペプチドの解析

    Grant number:06282241  1994

    日本学術振興会  科学研究費助成事業 重点領域研究  重点領域研究

    鵜殿 平一郎

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    Grant amount:\3300000 ( Direct expense: \3300000 )

    Hsp70からATP依存性に遊離してきたペプチドのプールシークエンスの結果はN末1番目のアミノ酸はIle,Leu,Valの分岐鎖アミノ酸、及びAla,Pheの頻度も高くこれらのアミノ酸の量を合計すると全体の80%くらいを占める。2番目にはAsn,Asp,Glu,Gln,Lys,Ser,Thrなどの親水性のアミノ酸が位置する。Gly、Proは2ないし3番目から7番目くらいに高頻度に認められた。この結果は4回おこなったいいずれの実験でも同様であった。ER内にあるgp96からTFA処理にて得られたペプチドのプールシークエンスからもほぼ同様の結果が得られた。このことはhsp70及びgp96のペプチド結合部位の構造が類似である可能性を示唆する。
    さらにhsp70から遊離してきたペプチドをC18逆相カラムにより分離し一部のペプチドピークをエドマン分解法にてそのアミノ酸配列を決定した。これまでにRas蛋白、hsp84、Annexin、Laminin、などに由来する約15本のペプチドのアミノ酸配列が決まったがそのほとんどは内因性由来の蛋白分子からきている。またタンデム質量分析器を用いてペプチドの分子量をみたところ約800から2000の範囲に多くのペプチドが観察された。Hsp70については従来からクラスIIの抗原提示に関与していることが言われてきたが、これらペプチドの解析の結果からクラスI及びクラスII両方の経路に関与している可能性が考えられる。さらに小胞体にあるgp96,Bipの結合ペプチドの構造決定が必要である。これらの結果をもとに、ストレス蛋白に結合している腫瘍抗原ペプチドの検出を行なうことも検討中である。

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  • 分子シャペロンと抗原のプロセッシング

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  • ストレス蛋白を用いたワクチン開発

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  • プロテアソームin vitro再構築

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  • プロテオーム解析特にLC/MS

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  • 生物活性の高いリコンビナント蛋白のrefolding 法の確立

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  • 癌の遺伝子治療及び免疫治療

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  • HLA 提示ペプチドの予測技術の確立

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  • 細胞傷害性T 細胞の誘導法

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  • ストレス蛋白の精製・調整法

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  • 免疫研究に用いられる一般的研究手法

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  • MethodsIn for vitro reconstitution of 26S proteasome

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  • 分子シャペロンHsp90, hsp70,hsp40, gp96、さらにプロテアソームとその活性化分子PA28 を対象に研究を推進している。これらの分子群を介した細胞内抗原プロセシング、蛋白分解の詳細を明らかにする。即ち、20S プロテアソームに結合する上記cap 分子の違いにより、産生される抗原ペプチドのレパトリーにどのような差異が生じるのか、そのことが疾患感受性にどうつながるのかを解析

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  • 分子シャペロン及びPA28 の性質を応用し、癌・感染症に対するワクチン開発を行う。技術的にはこれら分子の細胞からの精製・調整と免疫学的及び生化学的解析を行っている

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  • MS を用いたプロテオーム解析とマイクロアレイ解析を併用し、蛋白分解とRNA 恒常性に及ぼす分子シャペロン及びPA28 の影響を網羅的に解析

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  • Refolding method for recombinant proteins that keep high physiological activity

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  • Gene therapy and immunotherapy for cancer

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  • Algorithm establishment for HLA presentable pepitdes

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  • Vaccine development by use of stress proteins

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  • general methods used for immunological experiments

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  • proteome analysis using LC/MS

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  • purification and preparations of stress proteins

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  • Analysis of molecular chaperones in MHC class I antigen processing

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  • Vaccine development by use of molecular chaperones

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  • Proteome analysis of cellular protein expressions influenced by overexpression of PA28 and molecular chaperones

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  • inducing methods for cytotoxic T lymphocytes

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  • Heat Shock Protein and Immune response

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  • Molecular chaperones and antigen processing

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