研究者詳細 - 藤原　英晃

論文 - 藤原　英晃

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Oral Inflammation and Microbiome Dysbiosis Exacerbate Chronic Graft-versus-host Disease. 国際誌

Yui Kambara, Hideaki Fujiwara, Akira Yamamoto, Kazuyoshi Gotoh, Shuma Tsuji, Mari Kunihiro, Tadashi Oyama, Toshiki Terao, Ayame Sato, Takehiro Tanaka, Daniel Peltier, Keisuke Seike, Hisakazu Nishimori, Noboru Asada, Daisuke Ennishi, Keiko Fujii, Nobuharu Fujii, Ken-Ichi Matsuoka, Yoshihiko Soga, Pavan Reddy, Yoshinobu Maeda

Blood 2024年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

The oral microbiota, second in abundance to the gut, is implicated in chronic systemic diseases, but its specific role in GVHD pathogenesis has been unclear. Our study finds that mucositis-induced oral dysbiosis in patients post-hematopoietic cell transplantation associated with increased chronic GVHD (cGVHD) even in patients receiving post-transplant cyclophosphamide. In murine HCT models, oral dysbiosis caused by bilateral molar ligatures exacerbated cGVHD and increased bacterial load in the oral cavity and gut with Enterococcaceae significantly increasing in both organs. In this model, the migration of Enterococcaceae to cervical lymph nodes (LNs) both pre- and post-transplantation activated antigen-presenting cells (APCs), thereby promoting the expansion of donor-derived inflammatory T cells. Based on these results, we hypothesize that pathogenic bacteria increased in the oral cavity might not only exacerbate local inflammation but also enhance systemic inflammation throughout the HCT course. Additionally, these bacteria translocated to the gut and formed ectopic colonies, further amplifying systemic inflammation. Furthermore, interventions targeting the oral microbiome mitigated murine cGVHD. Collectively, our findings highlight the importance of oral dysbiosis in cGVHD and suggest that modulation of the oral microbiome during transplantation may be an effective approach for preventing or treating cGVHD.

DOI： 10.1182/blood.2024024540

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Sigle Agent of Posttransplant Cyclophosphamide Without Calcineurin Inhibitor Controls Severity of Experimental Chronic GVHD. 査読

Kyosuke Saeki, Hideaki Fujiwara, Keisuke Seike, Taiga Kuroi, Hisakazu Nishimori, Takehiro Tanaka, Ken-Ichi Matsuoka, Nobuharu Fujii, Yoshinobu Maeda

Acta medica Okayama 78 ( 2 ) 123 - 134 2024年4月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity following allogeneic hematopoietic cell transplantation (HCT), but its pathogenesis remains unclear. Recently, haplo-identical HCT with post-transplant cyclophosphamide (Haplo-HCT with PTCY) was found to achieve a low incidence rate of acute GVHD and chronic GVHD. However, while the pathogenesis of acute GVHD following Haplo-HCT with PTCY has been well investigated, that of chronic GVHD remains to be elucidated, especially in HLA-matched HCT with PTCY. Based on its safety profile, PTCY is currently applied for the human leucocyte antigen (HLA)-matched HCT setting. Here, we investigated the mechanisms of chronic GVHD following HLA-matched HCT with PTCY using a well-defined mouse chronic GVHD model. PTCY attenuated clinical and pathological chronic GVHD by suppressing effector T-cells and preserving regulatory T-cells compared with a control group. Additionally, we demonstrated that cyclosporine A (CsA) did not show any additional positive effects on attenuation of GVHD in PTCY-treated recipients. These results suggest that monotherapy with PTCY without CsA could be a promising strategy for the prevention of chronic GVHD following HLA-matched HCT.

DOI： 10.18926/AMO/66915

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Impact of oral microbiota on pathophysiology of GVHD 招待査読国際誌

Akira Yamamoto, Yui Kambara, Hideaki Fujiwara

Frontiers in Immunology 14 1132983 - 1132983 2023年3月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Frontiers Media SA

Allogeneic transplantation of hematopoietic cells is the only curative therapy for several hematopoietic disease in which patients receive cytotoxic conditioning regimens followed by infusion of hematopoietic stem cells. Although the outcomes have improved over the past decades, graft-versus-host-disease (GVHD), the most common life-threatening complication, remains a major cause of non-relapse morbidity and mortality. Pathophysiology of acute GVHD characterized by host antigen-presenting cells after tissue damage and donor T-cells is well studied, and additionally the importance of recipient microbiota in the intestine is elucidated in the GVHD setting. Oral microbiota is the second most abundant bacterial flora in the body after the intestinal tract, and it is related to chronic inflammation and carcinogenesis. Recently, composition of the oral microbiome in GVHD related to transplantation has been characterized and several common patterns, dysbiosis and enrichment of the specific bacterial groups, have been reported. This review focuses on the role of the oral microbiota in the context of GVHD.

DOI： 10.3389/fimmu.2023.1132983

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Ambient oxygen levels regulate intestinal dysbiosis and GVHD severity after allogeneic stem cell transplantation. 査読国際誌

Keisuke Seike, Anders Kiledal, Hideaki Fujiwara, Israel Henig, Marina Burgos da Silva, Marcel R M van den Brink, Robert Hein, Matthew Hoostal, Chen Liu, Katherine Oravecz-Wilson, Emma Lauder, Lu Li, Yaping Sun, Thomas M Schmidt, Yatrik M Shah, Robert R Jenq, Gregory Dick, Pavan Reddy

Immunity 56 ( 2 ) 353 - 368 2023年2月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

The severity of T cell-mediated gastrointestinal (GI) diseases such as graft-versus-host disease (GVHD) and inflammatory bowel diseases correlates with a decrease in the diversity of the host gut microbiome composition characterized by loss of obligate anaerobic commensals. The mechanisms underpinning these changes in the microbial structure remain unknown. Here, we show in multiple specific pathogen-free (SPF), gnotobiotic, and germ-free murine models of GI GVHD that the initiation of the intestinal damage by the pathogenic T cells altered ambient oxygen levels in the GI tract and caused dysbiosis. The change in oxygen levels contributed to the severity of intestinal pathology in a host intestinal HIF-1α- and a microbiome-dependent manner. Regulation of intestinal ambient oxygen levels with oral iron chelation mitigated dysbiosis and reduced the severity of the GI GVHD. Thus, targeting ambient intestinal oxygen levels may represent a novel, non-immunosuppressive strategy to mitigate T cell-driven intestinal diseases.

DOI： 10.1016/j.immuni.2023.01.007

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Mitochondrial complex II in intestinal epithelial cells regulates T cell-mediated immunopathology. 査読国際誌

Hideaki Fujiwara, Keisuke Seike, Michael D Brooks, Anna V Mathew, Ilya Kovalenko, Anupama Pal, Ho-Joon Lee, Daniel Peltier, Stephanie Kim, Chen Liu, Katherine Oravecz-Wilson, Lu Li, Yaping Sun, Jaeman Byun, Yoshinobu Maeda, Max S Wicha, Thomas L Saunders, Alnawaz Rehemtulla, Costas A Lyssiotis, Subramaniam Pennathur, Pavan Reddy

Nature immunology 22 ( 11 ) 1440 - 1451 2021年11月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

Intestinal epithelial cell (IEC) damage by T cells contributes to graft-versus-host disease, inflammatory bowel disease and immune checkpoint blockade-mediated colitis. But little is known about the target cell-intrinsic features that affect disease severity. Here we identified disruption of oxidative phosphorylation and an increase in succinate levels in the IECs from several distinct in vivo models of T cell-mediated colitis. Metabolic flux studies, complemented by imaging and protein analyses, identified disruption of IEC-intrinsic succinate dehydrogenase A (SDHA), a component of mitochondrial complex II, in causing these metabolic alterations. The relevance of IEC-intrinsic SDHA in mediating disease severity was confirmed by complementary chemical and genetic experimental approaches and validated in human clinical samples. These data identify a critical role for the alteration of the IEC-specific mitochondrial complex II component SDHA in the regulation of the severity of T cell-mediated intestinal diseases.

DOI： 10.1038/s41590-021-01048-3

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RNA-seq of human T cells after hematopoietic stem cell transplantation identifies Linc00402 as a regulator of T cell alloimmunity. 国際誌

Daniel Peltier, Molly Radosevich, Visweswaran Ravikumar, Sethuramasundaram Pitchiaya, Thomas Decoville, Sherri C Wood, Guoqing Hou, Cynthia Zajac, Katherine Oravecz-Wilson, David Sokol, Israel Henig, Julia Wu, Stephanie Kim, Austin Taylor, Hideaki Fujiwara, Yaping Sun, Arvind Rao, Arul M Chinnaiyan, Daniel R Goldstein, Pavan Reddy

Science translational medicine 13 ( 585 ) 2021年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Mechanisms governing allogeneic T cell responses after solid organ and allogeneic hematopoietic stem cell transplantation (HSCT) are incompletely understood. To identify lncRNAs that regulate human donor T cells after clinical HSCT, we performed RNA sequencing on T cells from healthy individuals and donor T cells from three different groups of HSCT recipients that differed in their degree of major histocompatibility complex (MHC) mismatch. We found that lncRNA differential expression was greatest in T cells after MHC-mismatched HSCT relative to T cells after either MHC-matched or autologous HSCT. Differential expression was validated in an independent patient cohort and in mixed lymphocyte reactions using ex vivo healthy human T cells. We identified Linc00402, an uncharacterized lncRNA, among the lncRNAs differentially expressed between the mismatched unrelated and matched unrelated donor T cells. We found that Linc00402 was conserved and exhibited an 88-fold increase in human T cells relative to all other samples in the FANTOM5 database. Linc00402 was also increased in donor T cells from patients who underwent allogeneic cardiac transplantation and in murine T cells. Linc00402 was reduced in patients who subsequently developed acute graft-versus-host disease. Linc00402 enhanced the activity of ERK1 and ERK2, increased FOS nuclear accumulation, and augmented expression of interleukin-2 and Egr-1 after T cell receptor engagement. Functionally, Linc00402 augmented the T cell proliferative response to an allogeneic stimulus but not to a nominal ovalbumin peptide antigen or polyclonal anti-CD3/CD28 stimulus. Thus, our studies identified Linc00402 as a regulator of allogeneic T cell function.

DOI： 10.1126/scitranslmed.aaz0316

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ER-to-Golgi transport and SEC23-dependent COPII vesicles regulate T cell alloimmunity. 国際誌

Stephanie Kim, Rami Khoriaty, Lu Li, Madison McClune, Theodosia A Kalfa, Julia Wu, Daniel Peltier, Hideaki Fujiwara, Yaping Sun, Katherine Oravecz-Wilson, Richard A King, David Ginsburg, Pavan Reddy

The Journal of clinical investigation 131 ( 2 ) 2021年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

T cell-mediated responses are dependent on their secretion of key effector molecules. However, the critical molecular determinants of the secretion of these proteins are largely undefined. Here, we demonstrate that T cell activation increases trafficking via the ER-to-Golgi pathway. To study the functional role of this pathway, we generated mice with a T cell-specific deletion in SEC23B, a core subunit of coat protein complex II (COPII). We found that SEC23B critically regulated the T cell secretome following activation. SEC23B-deficient T cells exhibited a proliferative defect and reduced effector functions in vitro, as well as in experimental models of allogeneic and xenogeneic hematopoietic cell transplantation in vivo. However, T cells derived from 3 patients with congenital dyserythropoietic anemia II (CDAII), which results from Sec23b mutation, did not exhibit a similar phenotype. Mechanistic studies demonstrated that unlike murine KO T cells, T cells from patients with CDAII harbor increased levels of the closely related paralog, SEC23A. In vivo rescue of murine KO by expression of Sec23a from the Sec23b genomic locus restored T cell functions. Together, our data demonstrate a critical role for the COPII pathway, with evidence for functional overlap in vivo between SEC23 paralogs in the regulation of T cell immunity in both mice and humans.

DOI： 10.1172/JCI136574

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Crosstalk Between Intestinal Microbiota Derived Metabolites and Tissues in Allogeneic Hematopoietic Cell Transplantation. 招待査読国際誌

Hideaki Fujiwara

Frontiers in immunology 12 703298 - 703298 2021年

記述言語：英語掲載種別：研究論文（学術雑誌）

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an evidence based- cellular immunotherapy for hematological malignancies. Immune reactions not only promote graft-versus-tumor effects that kill hematological malignant cells but also graft-versus-host disease (GVHD) that is the primary complication characterized by systemic organ damages consisting of T-cells and antigen presenting cells (APCs) activation. GVHD has long been recognized as an immunological reaction that requires an immunosuppressive treatment targeting immune cells. However immune suppression cannot always prevent GVHD or effectively treat it once it has developed. Recent studies using high-throughput sequencing technology investigated the impact of microbial flora on GVHD and provided profound insights of the mechanism of GVHD other than immune cells. Allo-HSCT affects the intestinal microbiota and microbiome-metabolome axis that can alter intestinal homeostasis and the severity of experimental GVHD. This axis can potentially be manipulated via dietary intervention or metabolites produced by intestinal bacteria affected post-allo-HSCT. In this review, we discuss the mechanism of experimental GVHD regulation by the complex microbial community-metabolites-host tissue axis. Furthermore, we summarize the major findings of microbiome-based immunotherapeutic approaches that protect tissues from experimental GVHD. Understanding the complex relationships between gut microbiota-metabolites-host tissues axis provides crucial insight into the pathogenesis of GVHD and advances the development of new therapeutic approaches.

DOI： 10.3389/fimmu.2021.703298

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Host NLRP6 exacerbates graft-versus-host disease independent of gut microbial composition. 査読国際誌

Nature Microbiology 4 ( 5 ) 800 - 812 2019年5月

Microbial metabolite sensor GPR43 controls severity of experimental GVHD. 査読国際誌

Nature communications 9 ( 1 ) 3674 - 3674 2018年9月

Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease. 査読国際誌

Nature Immunology 17 ( 5 ) 505 - 513 2016年5月

Anti-IL-12/23 p40 antibody attenuates experimental chronic graft versus host disease via suppression of IFN-γ/IL-17-producing cells. 査読国際誌

Journal of Immunology 194 ( 3 ) 1357 - 63 2015年2月

Programmed Death-1 Pathway in Host Tissues Ameliorates Th17/Th1-Mediated Experimental Chronic Graft-versus-Host Disease. 査読国際誌

Journal of Immunology 193 ( 5 ) 2565 - 73 2014年9月

Host Tissue PD-1 Pathway Contribute To Murine Chronic Graft-Versus-Host Disease Via Th1+Th17+ Cells 査読

Hideaki Fujiwara, Yoshinobu Maeda, Koichiro Kobayashi, Hisakazu Nishimori, Ken-ichi Matsuoka, Nobuharu Fujii, Eisei Kondo, (Takehiro Tanaka), ( Lieping Chen), ( Miyuki Azuma), ( Hideo Yagita), Mitsune Tanimoto

Blood 122 ( 21 ) 2013年11月

Gross hematopyuria presenting as a first symptom due to the bladder infiltration of extranodal Burkitt's lymphoma. 査読国際誌

Journal of Clinical Oncology 28 ( 16 ) e252-3 2010年6月

Severe hypophosphatemia following idecabtagene vicleucel regardless of the severity of cytokine release syndrome

Kenta Hayashino, Wataru Kitamura, Nobuharu Fujii, Toshiki Terao, Hiroki Kobayashi, Chihiro Kamoi, Takumi Kondo, Keisuke Seike, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Keiko Fujii, Yoshinobu Maeda

Cytotherapy 2025年1月

Outcomes of allogeneic SCT versus tisagenlecleucel in patients with R/R LBCL and poor prognostic factors.

Kenta Hayashino, Toshiki Terao, Hisakazu Nishimori, Wataru Kitamura, Hiroki Kobayashi, Chihiro Kamoi, Keisuke Seike, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Keiko Fujii, Nobuharu Fujii, Ken-Ichi Matsuoka, Yoshinobu Maeda

International journal of hematology 2024年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

This study investigated the efficacy of tisagenlecleucel (tisa-cel) and allogeneic hematopoietic stem cell transplantation (allo-SCT) for patients with relapsed and/or refractory (r/r) large B-cell lymphoma (LBCL) with poor prognostic factors, defined as performance status (PS) ≥ 2, multiple extranodal lesions (EN), chemorefractory disease, or higher lactate dehydrogenase (LDH). Overall, the allo-SCT group demonstrated worse progression-free survival (PFS), higher non-relapse mortality, and a similar relapse/progression rate. Notably, the tisa-cel group showed better PFS than the allo-SCT group among patients with chemorefractory disease (3.2 vs. 2.0 months, p = 0.092) or higher LDH (4.0 vs. 2.0 months, p = 0.018), whereas PFS in the two cellular therapy groups was similar among those with PS ≥ 2 or multiple EN. Survival time after relapse post-cellular therapy in patients with poor prognostic factors was 1.6 with allo-SCT and 4.6 months with tisa-cel. These findings were confirmed in a propensity score matching cohort. In conclusion, tisa-cel resulted in better survival than allo-SCT in patients with poor prognostic factors. However, patients who relapsed post-cellular therapy had dismal outcomes regardless of therapy. Further strategies are warranted to improve outcomes in these patients.

DOI： 10.1007/s12185-024-03888-9

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中枢神経原発リンパ腫におけるplasmablastサブポピュレーションの分子学的特性について

小林宏紀, 千々松良太, 直井友亮, 大谷理浩, 水田亮, 藤井謙太郎, 石田穣治, 村上裕之, 氏家英貴, 池内一廣, 浦田知宏, 清家圭介, 藤原英晃, 淺田騰, 藤井伸治, 松岡賢市, 佐藤康晴, 前田嘉信, 遠西大輔

日本血液学会学術集会 86回 O3 - 2 2024年10月

Simulation-based Bone Marrow Aspiration and Trephine Biopsy Education for Medical Students: A Non-randomized Controlled Trial.

Akira Yamamoto, Hisakazu Nishimori, Keisuke Seike, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Keiko Fujii, Nobuharu Fujii, Ken-Ichi Matsuoka, Yoshinobu Maeda

Internal medicine (Tokyo, Japan) 2024年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Introduction Despite the critical role of bone marrow aspiration and a trephine biopsy (BMAT) in the diagnosis and management of hematological diseases, research on effective teaching methods is limited. Medical students traditionally learn to perform BMAT through observation and replication, which poses a risk to patient safety. Therefore, we developed a novel BMAT simulator for undergraduate medical students using a simulation-based education program. Methods This program, designed for fourth- and fifth-year medical students at Okayama University Medical School, included pre-study materials and one hour of simulation training. Internists practicing hematology served as the controls. Before and after the simulation training, the students completed questionnaires regarding self-confidence, self-evaluation, interest, and knowledge. The procedures were evaluated objectively using a checklist at the end of the program. Results There were significant improvements in self-evaluation, self-confidence, interest, and knowledge acquisition after the simulation program (p≤0.001). The checklist revealed that the mean overall proficiency level of the students was 76.9%, which was significantly higher than that of internists (63.5%) (p≤0.01). Conclusion Our simulation-based education program using the novel BMAT simulator improved medical students' BMAT knowledge and skills.

DOI： 10.2169/internalmedicine.3998-24

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Activated CD4<sup>+</sup> T Cell Proportion in the Peripheral Blood Correlates with the Duration of Cytokine Release Syndrome and Predicts Clinical Outcome after Chimeric Antigen Receptor T Cell Therapy

Wataru Kitamura, Noboru Asada, Shuntaro Ikegawa, Hideaki Fujiwara, Chihiro Kamoi, Daisuke Ennishi, Hisakazu Nishimori, Keiko Fujii, Nobuharu Fujii, Ken-ichi Matsuoka, Yoshinobu Maeda

Internal Medicine 63 ( 13 ) 1863 - 1872 2024年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Japanese Society of Internal Medicine

Objective Chimeric antigen receptor (CAR) T cell therapy is an emerging and effective therapy for relapsed or refractory diffuse large B cell lymphoma (R/R DLBCL). The characteristic toxicities of CAR T cell therapy include cytokine release syndrome (CRS) and prolonged cytopenia. We investigated the factors associated with these complications after CAR T cell therapy by analyzing lymphocyte subsets following CAR T cell infusion. Methods We retrospectively analyzed peripheral blood samples on days 7, 14, and 28 after tisagenlecleucel (tisa-cel) infusion by flow cytometry at our institution between June 2020 and September 2022. Patients Thirty-five patients with R/R DLBCL who received tisa-cel therapy were included. Results A flow cytometry-based analysis of blood samples from these patients revealed that the proportion of CD4+CD25+CD127+ T cells (hereafter referred to as "activated CD4+ T cells" ) among the total CD4+ T cells on day 7 after tisa-cel infusion correlated with the duration of CRS (r=0.79, p<0.01). In addition, a prognostic analysis of the overall survival (OS) using time-dependent receiver operating characteristic curves indicated a significantly more favorable OS and progression-free survival of patients with a proportion of activated CD4+ T cells among the total CD4+ T cells <0.73 (p=0.01, and p<0.01, respectively). Conclusion These results suggest that the proportion of activated CD4+ T cells on day 7 after tisa-cel infusion correlates with the CRS duration and predicts clinical outcomes after CAR T cell therapy. Further studies with a larger number of patients are required to validate these observations.

DOI： 10.2169/internalmedicine.2556-23

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