Comprehensive analysis of role of dendritic cells and target cells in graft-versus-host disease and graft-versus-leukemia
| 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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Report
(4 results)
Research Products
(78 results)
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[Presentation] Host plasmacytoid or conventional dendritic cells alone are sufficient to initiate graft-versus-host disease2007
Author(s)
M., Koyama, D., Hashimoto, K., Aoyama, K., Matsuoka, K., Karube, K., Takeda, K., Ohshima, M., Tanimoto, M., Harada, T., Teshima
Organizer
49th Annual Meeting of ASH
Place of Presentation
Atlanta, USA
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Presentation] Host plasmacytoid or conventional dendritic cells alone are sufficient to initiate graft-versus-host disease.2007
Author(s)
Koyama M, Hashimoto D, Aoyama K, Matsuoka K, Karube K, Takeda K, Ohshima K, Tanimoto M, Harada M, Teshima T
Organizer
49^<th> Annual Meeting of The American Society of Hematology
Place of Presentation
Atlanta, USA
Related Report
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