| Project/Area Number |
17390280
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | Kyushu University |
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Principal Investigator |
TESHIMA Takanori Kyushu University, Hospital, Associate Professor (40284096)
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| Co-Investigator(Kenkyū-buntansha) |
TANIMOTO Mistune Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Medicine, Biopathological Science, Professor (10240805)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥16,430,000 (Direct Cost: ¥15,200,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2007: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2006: ¥4,300,000 (Direct Cost: ¥4,300,000)
Fiscal Year 2005: ¥6,800,000 (Direct Cost: ¥6,800,000)
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| Keywords | graft-versus-host disease / graft-versus-leukemia / sphingosin-1-nhoshate / FTY720 / activation-induced cell death / plasmacvtoid dendritic cell / MyD88 / TRIF / graft-versus-hostdisease / dendritic cell / lymph nodes |
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| Research Abstract |
Interactions of T cells and dendritic cells (DCs) between donors and hosts are critical to initiate allogeneic T cell responses, such as graft rejection and graft-versus-host disease (GVHD) in allogeneic transplantation of solid organs and hematopoietic stem cells (HSCs). FTY720 is a novel immunosuppressant that improves the outcomes after solid organ and bone marrow transplantation(BMT)due to the sequestration of T cells into LNs. We tested the hypothesis that the sequestration of donor T cells in LNs by FTY720 would enhance their interaction with host APCs, thus causing a greater degree of activation-induced apoptosis of alloreactive T cells, and thereby resulting in a reduction of GVHD. The short-term administration of FTY720 improved the recipient survival after allogeneic BMT. FTY720-treatment facilitated a rapid contraction of the donor T cell pool in association with an increased degree of apoptosis of donor T cells. The donor T cell reactivity to host alloantigens was diminishe
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d in host's LNs and adoptive transfer of donor T cells isolated from LNs of FTY720-treated recipients of allogeneic BMT induced less severe GVHD in secondary recipients than the transfer from controls. Caspase-dependent apoptosis was involved in this mechanism because FTY720-induced protection was abrogated when pan-caspase inhibitor was administered. These findings thus demonstrate the presence of a novel mechanism by which FTY720 modulates the allogeneic T cell responses: namely, by the induction of activation-induced apoptosis of alloreactive T cells in LNs.
We next tested the role of MHC and alloantigen expression on host non-hematopoietic cells on graft-versus-leukemia (GVL) effects after allogeneic BMT using chimeric mice expressing alloantigens on hematopoietic cells 'alone. Alloantigen expression on non-hematopoietic cells drives donor T cells into activation-induced apoptosis and leads to dysfunctional cytotoxic effector function, resulting in a reduction of GVL activity. The superior GVL activity observed in chimeric mice that lacked alloantigen expression on non-hematopoietic cells was abrogated when non-hematopoietic cells lack expression of MHC class I molecules. The results demonstrate that maximum GVL effects require expression of MHC molecules on APCs in the absence of alloantigens on non-hematopoietic cells. These results unveiled the previously unrecognized significance of MHC and alloantigen expression on non-hematopoietic cells in GVL effects and provide an important framework to understand pathophysiology of GVL for the separation of GVL from GVHD. DCs can be divided into two main subpopulations; conventional DCs (cDCs) and plasmacytoid DCs(pDCs). cDCs can prime naive T cells, whereas pDCs can be tolerogenic in organ transplantation. We tested whether pDCs could prime allogeneic T cells in mouse models of allogeneic HSC transplantation by an add-back study of MHC-expressing pDCs into MHC class II and 2-micmglobulin deficient mice that were resistant to CD4 and CD8-deoendent GVHD, respectively. pDCs alone were sufficient of pDCs that was independent on toll-like receptor signaling. Thus pDCs can prime allogeneic T cells in an inflamed environment and these results provide important information for developing strategies aimed at inactivating DCs to prevent GVHD. Less
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