Faculty Profiles - MAEDA Yoshinobu

A crucial role for antigen-presenting cells and alloantigen expression in graft-versus-leukemia responses International journal

P Reddy, Y Maeda, C Liu, OI Krijanovski, R Korngold, JLM Ferrara

NATURE MEDICINE 11 ( 11 ) 1244 - 1249 2005.11

Language：English Publisher：NATURE PUBLISHING GROUP

Graft-versus-leukemia ( GVL) response after allogeneic bone marrow transplantation ( BMT) represents one of the most potent forms of immunotherapy against malignant diseases(1). Antigen-presenting cells ( APCs) are crucial for the induction of graft-versus-host disease ( GVHD)(2-6), the most serious complication of allogeneic BMT, but their role in GVL responses is unclear. Using a series of clinically relevant mouse GVL tumor models, we found that APCs and alloantigen expression on tumors are crucial for GVL. Moreover, APCs of host origin predominated in GVL responses although donor APCs contributed as the acuity of tumor burden decreased.

DOI： 10.1038/nm1309

Homeostatic proliferation of donor T cells reduces their capacity for inducing acute graft-versus-host disease.

Y Maeda, T Teshima, D Hashimoto, M Tammoto, P Reddy

BLOOD 106 ( 11 ) 378A - 378A 2005.11

Critical role of host gamma delta T cells in experimental acute graft-versus-host disease International journal

Y Maeda, P Reddy, KP Lowler, C Liu, DK Bishop, JLM Ferrara

BLOOD 106 ( 2 ) 749 - 755 2005.7

Language：English Publisher：AMER SOC HEMATOLOGY

gamma delta T cells localize to target tissues of graft-versus-host disease (GVHD) and therefore we investigated the role of host gamma delta T cells in the pathogenesis of acute GVHD in several well-characterized allogeneic bone marrow transplantation (BMT) models. Depletion of host gamma delta T cells in wild-type (wt) B6 recipients by administration of anti-T-cell receptor (TCR) gamma delta monoclonal antibody reduced GVHD, and gamma delta T-cell-deficient (gamma delta(-/-)) BM transplant recipients experienced markedly improved survival compared with normal controls (63% vs 10%, P <.001). gamma delta T cells were responsible for this difference because reconstitution of gamma delta(-/-) recipients with gamma delta T cells restored GVHD mortality. gamma delta(-/-) recipients showed decreased serum levels of tumor necrosis factor alpha (TNF-alpha), less GVHD histopathologic damage, and reduced donor T-cell expansion. Mechanistic analysis of this phenomenon demonstrated that dendritic cells (DCs) from gamma delta(-/-) recipients exhibited less allostimulatory capacity compared to wt DCs after irradiation. Normal DCs derived from BM caused greater allogeneic T-cell proliferation when cocultured with gamma delta T cells than DCs cocultured with medium alone. This enhancement did not depend on interferon,gamma (IFN-gamma), TNF-alpha, or CD40 ligand but did depend on cell-to-cell contact. These data demonstrated that the host gamma delta T cells exacerbate GVHD by enhancing the allostimulatory capacity of host antigen-presenting cells.

DOI： 10.1182/blood-2004-10-4087

Both perforin and Fas ligand are required for the regulation of alloreactive CD8(+) T cells during acute graft-versus-host disease International journal

Y Maeda, RB Levy, P Reddy, C Liu, SG Clouthier, F Teshima, JLM Ferrara

BLOOD 105 ( 5 ) 2023 - 2027 2005.3

Language：English Publisher：AMER SOC HEMATOLOGY

Fas ligand (FasL) and perforin pathways not only are the major mechanisms of T cell-mediated cytotoxicity but also are involved in homeostatic regulation of these T cells. In the present study, we tested whether CD8(+) donor T cells that are deficient in both perforin and FasL (cytotoxic double deficient [cdd]) could induce graft-versus-host disease (GVHD) in a major histocompatibility complex class I-mismatched lethally irradiated murine model. Interestingly, recipients of cdd CD8(+) T cells demonstrated significantly greater serum levels of interferon gamma and tumor necrosis factor alpha and histopathologic damage from GVHD than wild-type (wt) T cells on day 30 after allogeneic bone marrow transplantation (P < .05). Wt and either perforin-deficient or FasL-deficient CD8(+) T cells expanded early after transplantation followed by a contraction phase in which the majority of expanded CD8(+) T cells were eliminated. In contrast, cdd CD8(+) T cells exhibited prolonged expansion and reduced apoptosis to alloantigen stimulation in vivo and in vitro. Together these results suggest that donor cdd CD8(+) T cells expand continuously and cause lethal GVHD, and that both perforin and Fast-are required for the contraction of alloreactive CD8(+) T cells. (C) 2005 by The American Society of Hematology.

DOI： 10.1182/blood-2004-08-3036

Serum hemoglobin level determined at the first presentation is a poor prognostic indicator in patients with lung cancer

Aoe K, Hiraki A, Maeda T, Katayama H, Fujiwara K, Tabata M, Kiura K, Ueoka H, Tanimoto M

Intern Med 2005

Safety and efficacy of gefitinib treatment in elderly patients with non--small--cell lung cancer: Okayama Lung Cancer Study Group Experience

Hotta K, Ueoka H, Kiura K, Tabata M, Ogino A, Umemura S, Harita S, Gemba K, Yonei T, Bessho A, Maeda T, Tanimoto M

Acta Oncol 2005

Paradoxical effects of interleukin-18 on the severity of acute graft-versus-host disease mediated by CD4(+) and CD8(+) T-cell subsets after experimental allogeneic bone marrow transplantation International journal

CK Min, Y Maeda, K Lowler, C Liu, S Clouthier, D Lofthus, E Weisiger, JLM Ferrara, P Reddy

BLOOD 104 ( 10 ) 3393 - 3399 2004.11

Language：English Publisher：AMER SOC HEMATOLOGY

Administration of exogenous interleukin-18 (IL-18) regulates experimental acute graft-versus-host disease (GVHD) in a Fas-dependent manner when donor CD4(+) T cells are required for mortality after experimental allogeneic bone marrow transplantation (BMT). However, CD4(+) and CD8(+) T cells can induce acute GVHD after clinical allogeneic BMT, and the role of IL-18 in CD8(+)-mediated acute GVHD is unknown. We, therefore, determined the role of IL-18 in GVHD mediated by CD4(+) or CD8(+) T cells across major histocompatibility complex (MHC) class II- and class I-disparate allogeneic BMT, respectively. Administering IL-18 significantly increased survival in CD4(+)-mediated GVHD but reduced survival in CD8(+)-mediated GVHD. This increase in deaths was associated with significantly greater clinical, biochemical, and histopathologic parameters of GVHD damage and was independent of Fas expression on donor T cells. Administering IL-18 significantly enhanced allospecific cytotoxic function and expansion of CD8(+) cells. Endogenous IL-18 was critical to GVHD mediated by CD8(+) donor T cells because IL-18 receptor-deficient donors caused significantly less GVHD but exacerbated CD4(+)-mediated, GVHD-related death. Furthermore, administering anti-IL-18 monoclonal antibody significantly reduced CD8(+)-mediated, GVHD-related death. Together these findings demonstrate that IL-18 has paradoxical effects on CD4(+) and CD8(+) cell-mediated GVHD. (C) 2004 by The American Society of Hematology.

DOI： 10.1182/blood-2004-02-0763

Perforin and Fas ligand are required for the regulation of alloreactive CD8(+) T cells.

Y Maeda, RB Levy, P Reddy, C Liu, T Teshima, JLM Ferrara

BLOOD 104 ( 11 ) 834A - 834A 2004.11

Host dendritic cells alone are sufficient to initiate acute graft-versus-host disease International journal

UA Duffner, Y Maeda, KR Cooke, P Reddy, R Ordemann, C Liu, JLM Ferrara, T Teshima

JOURNAL OF IMMUNOLOGY 172 ( 12 ) 7393 - 7398 2004.6

Language：English Publisher：AMER ASSOC IMMUNOLOGISTS

Alloantigen expression on host APCs is essential to initiate graft-vs-host disease (GVHD); however, critical APC subset remains to be elucidated. We compared the ability of dendritic cells (DCs) and B cells to initiate acute GVHD by an add-back study of MHC class II-expressing APCs (II+/+) into MHC class II-deficient (II-/-) mice that were resistant to CD4-dependent GVHD. Injection of host-derived, but not donor-derived, II+/+ DCs or host-derived II+/+ B cells, was sufficient to break GVHD resistance of II-/- mice and induced lethal acute GVHD. By contrast, host-derived II+/+ B cells, both naive and LPS stimulated, failed to induce activation or tolerance of donor CD4(+) T cells. Similarly, in a model of CD8-dependent GVHD across MHC class I mismatch injection of allogeneic DCs, but not B cells, induced robust proliferation of donor CD8(+) T cells and broke GVHD resistance of chimeric recipients in which APCs were syngeneic to donors. These results demonstrate that host-derived DCs are critical in printing donor CD4(+) and CD8(+) T cells to cause GVHD, and selective targeting of host DCs may be a promising strategy to prevent GVHD.

Peripheral blood circulating immature cell counts predict CD34+ cell yields in G-CSF-induced PBPC mobilization in healthy donors International journal

T Kozuka, K Ikeda, T Teshima, C Yoshida, K Shinagawa, K Kojima, K Matsuo, A Bessho, K Sunami, Y Hiramatsu, Y Maeda, T Noguchi, K Yamamoto, N Fujii, T Imai, KK Kusumoto, K Masuda, K Takenaka, F Ishimaru, K Niiya, N Koide, M Tanimoto, M Harada

TRANSFUSION 44 ( 4 ) 526 - 532 2004.4

Language：English Publisher：BLACKWELL PUBLISHING INC

BACKGROUND: It has been previously reported that the number of circulating immature cells (CIC) in peripheral blood (PB) estimates the number of CD34+ cells collected in G-CSIF plus chemotherapy-induced PBPC mobilization. The correlation of CIC counts in PB with CD34+ cell yield and its usefulness was evaluated in G-CSF-induced PBPC mobilization for healthy donors.
STUDY DESIGN AND METHODS: CIC counts in PB and CD34+ cell counts in the apheresis product from 122 collections were assessed, and the relationship between these two variables was evaluated with the Pearson rank correlation analysis, the chi-squared test, and the U-test.
RESULTS: CIC counts were correlated weakly with the number of CD34+ cells per L of blood processed in the apheresis product (Pearson rank correlation analysis; r = 0.357, p < 0.0001). When a level of 1.7 x 10(9) CICs per L was selected as a cutoff value, the sensitivity and specificity for collecting more than 20 x 10(6) CD34+ cells per L of blood processed were 63.6 and 77.5 percent, respectively.
CONCLUSION: The present study suggests that the number of CICs in PB may estimate the number of CD34+ cells collected. The data indicate that CIC counts above 1.7 x 10(9) per L can be used as a good predictor for PBPC collections containing more than 20 x 10(6) CD34+ cells per L of blood processed in a single apheresis procedure.

DOI： 10.1111/j.1537-2995.2004.03078.x

Histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect International journal

P Reddy, Y Maeda, K Hotary, C Liu, LL Reznikov, CA Dinarello, JLM Ferrara

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 101 ( 11 ) 3921 - 3926 2004.3

Language：English Publisher：NATL ACAD SCIENCES

Acute graft-versus-host disease (GVHD) and leukemic relapse are the two major obstacles to successful outcomes after allogeneic bone marrow transplantation (BMT), an effective therapy for hematological malignancies. Several studies have demonstrated that the dysregulation of proinflammatory cytokines and the loss of gastrointestinal tract integrity contribute to GVHD, whereas the donor cytotoxic responses are critical for graft-versus-leukemia (GVL) preservation. Suberoylanilide hydroxamic acid (SAHA) is currently in clinical trials as an antitumor agent, it inhibits the activity of histone deacetylases and at low doses exhibits anti inflammatory effects by reducing the production of proinflammatory cytokines. Using two well characterized mouse models of BMT, we have studied the effects of SAHA on GVHD severity and GVL activity. Administration of SAHA from day +3 to day +7 after BMT reduced serum levels of the proinflammatory cytokines and decreased intestinal histopathology, clinical severity, and mortality from acute GVHD compared with vehicle-treated animals. However, SAHA had no effect on donor T cell proliferative and cytotoxic responses to host antigens in vivo or in vitro. When mice received lethal doses of tumor cells at the time of BMT, administration of SAHA did not impair GVL activity and resulted in significantly improved leukemia-free survival by using two different tumor and donor/recipient combinations. These findings reveal a critical role for histone deacetylase inhibition in the proinflammatory events contributing to GVHD and suggest that this class of pharmacologic agents may provide a strategy to reduce GVHD while preserving cytotoxic T cell responses to host antigens and maintaining beneficial GVL effects.

DOI： 10.1073/pnas.0400380101

High frequency of allele-specific down-regulation of HLA class I expression in lung cancer cell lines.

Hiraki A, Fujii N, Murakami T, Kiura K, Aoe K, Yamane H, Masuda K, Maeda T, Sugi K, Darzynkiewicz Z, Tanimoto M, Harada M

Anticancer Res 2004

Early changes in gene expression profiles of hepatic GVHD uncovered by oligonucleotide microarrays International journal

T Ichiba, T Teshima, R Kuick, DE Misek, C Liu, Y Takada, Y Maeda, P Reddy, DL Williams, SM Hanash, JLM Ferrara

BLOOD 102 ( 2 ) 763 - 771 2003.7

Language：English Publisher：AMER SOC HEMATOLOGY

The liver, skin, and gastrointestinal tract are major target organs of acute graft-versus-host disease (GVHD), the major complication of allogeneic bone marrow transplantation (BMT). In order to gain a better understanding of acute GVHD in the liver, we compared the gene expression profiles of livers after experimental allogeneic and syngeneic BMT using oilgonucleotide microarray. At 35 days after allogeneic BMT when hepatic GVHD was histologically evident, genes related to cellular effectors and acute-phase proteins were up-regulated, whereas genes largely related to metabolism and endocrine function were down-regulated. At day 7 after BMT before the development of histologic changes in the liver, interferon gamma (IFN-gamma)-inducible genes, major histocompatibility (MHC) class II molecules, and genes related to leukocyte trafficking had been up-regulated. Immunohistochemistry demonstrated that expression of IFN-gamma protein itself was increased in the spleen but not in hepatic tissue. These results suggest that the increased expression of genes associated with the attraction and activation of donor T cells induced by IFN-gamma early after BMT is important in the initiation of hepatic GVHD in this model and provide new potential molecular targets for early detection and intervention of acute GVHD. (C) 2003 by The American Society of Hematology.

DOI： 10.1182/blood-2002-09-2748

Human herpes virus-8-negative primary effusion lymphoma in a patient with common variable immunodeficiency. International journal

Akiko Hisamoto, Hiromichi Yamane, Akio Hiraki, Yoshinobu Maeda, Nobuharu Fujii, Kenji Sasaki, Toshitugu Miyake, Takashi Sasaki, Tohru Nakamura, Katsuyuki Kiura, Mitsune Tanimoto, Haruhito Kamei

Leukemia & lymphoma 44 ( 11 ) 2019 - 22 2003

Language：English

Primary effusion lymphoma (PEL) is a newly described high-grade B cell lymphoma developing in association with human herpes virus type 8 (HHV-8) in human immunodeficiency virus (HIV)-infecting individuals. Common variable immunodeficiency (CVID) is a primary immunodeficiency disease characterized by reduced serum immunoglobulin and heterogeneous clinical features. The risk of cancer in CVID patients is increased. Here, we describe a PEL that developed in the pleural and pericardial cavities of an HIV-negative and HHV-8-negative patient with CVID.

DOI： 10.1080/1042819031000110955