Reduced allostimulatory activity of host antigen-presenting cells regulates the severity of graft-versus-host disease while preserving a graft-versus-leukemia effect
| Project/Area Number |
18591062
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Okayama University |
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Principal Investigator |
MAEDA Yoshinobu Okayama University, Hospital, Assistant Professor (60403474)
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| Co-Investigator(Kenkyū-buntansha) |
TANIMOTO Mitsune Okayama University, Department of Hematology and Oncology, Professor (10240805)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,910,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Keywords | GVHD / antigen presenting cells / GVL / 移植片対宿主病 |
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| Research Abstract |
The activation of donor T cells by host dendritic cells (DCs) is critical to the induction of graft-versus-host disease (GVHD). We firstly analyzed the ability of SAHA to suppress the stimulatory function of DCs in vitro. T cells proliferated less when co-cultured with SAHA treated DCs than with control DCs. SAHA treated DCs also secreted less IL-6, IL-12 and TNF-a. We next evaluated effect of SAHA co-culture on the phenotype of DCs. SAHA decreased the expression of CD40, MHC Class II and CD80 on DCs. We next evaluated whether SAHA suppress DCs and reduce the responses of allogeneic T cells in vivo. Recipients of SAHA treated DCs showed significantly reduced GVHD mortality and clinical scores.
T cells that undergo lymphopenia induced proliferation (LIP) are characterized by greater effector and anti-tumor function than naive T cells. But the ability of these T cells in causing GVHD is not known. We tested the hypothesis that donor T cells that had undergone LIP would cause more severe GVHD than naive T cells by utilizing well-characterized murine experimental models of allogeneic bone marrow transplantation (BMT). Contrary to our hypothesis, LIP of donor T cells either under non-inflammatory or irradiated conditions caused significantly reduced GVHD as determined by survival, clinical, pathological and biochemical parameters than naive T cells. Compared to naive donor T cells, ;LIP T cells demonstrated reduced expansion in vivo and in vitro after allogeneic BMT. The reduction in GVHD mortality and severity was observed across multiple strains after allogeneic BMT. In vivo mechanistic studies by cell depletion demonstrated that an increase in the CD44hi "memory" phenotype T cells and not the CD4+CD25+ T cell subset to be critical for the reduction in GVHD. These data demonstrate that LIP of T cells regulates acute GVHD severity in contrast to their ability to cause increased allograft rejection, autoimmunity or anti-tumor immunity.
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Report
(3 results)
Research Products
(11 results)
