| Budget Amount *help |
¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
Allogeneic stem cell transplantation requires an HLA-identical sibling. However, only about 25% of patients who need allogeneic stem cell transplantation (SCT) have such a donor. Thus, an HLA-haploidentical (2-3 antigen-mismatched) donor has been considered as an alternative donor. In unmanipulated HLA-haploidentical SCT, severe graft-versus-host disease (GVHD) is a major problem. Production of inflammatory cytokine in the peritransplantation period is a key factor for developing GVHD. We have planned to overcome severe GVHD through suppressing the production of cytokines by reducing intensity of conditioning treatment (nonmyeloablative), or by a use of intensified GVHD prophylaxis containing steroids.
In nonmyeloablative SCT using an HLA-haploidentical donor, we reported a 96.2% engraftment rate and 20% incidence of severe GVHD (Biol Blood Marrow Tr, 2006; 12: 1073). Furthermore, In HLA-haploidentical myeloablative SCT using intensified GVHD prophylaxis containing steroids, we obtained
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a 100% engraftment rate and a 36.7% incidence of severe GVHD (Exp Hematol, 2008: 36: 1). These results indicated that unmanipulated HLA-haploidentical SCT was feasible.
In order to clarify the pathophysiology of engraftment or GVHD in HLA-haploidentical SCT, we developed murine MHC-mismatched bone marrow transplantation system (B6C3F1(H-2^<b/k>)→BDF1(H-2^<b/d>)). In this system, recipient mice did or did not develop fatal GVHD depending on total body irradiation dose. We analyzed the kinetics of, and the characteristics of, donor T cells in secondary lymphoid organs, including spleen and lymph nodes as well as in GVHD-target organs, including small and large intestines, liver and skin. As a result, GVHD mice were found to have massive invasive donor T cells in involved organs, although there was no difference in the extent of proliferation of T cells in secondary lymphoid organs between GVHD and non-GVHD mice. Thus, GVHD was found to occur depending on the extent of inflammation of GVHD-target organs. Less
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