| Project/Area Number |
11671179
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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 |
General surgery
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| Research Institution | Nara Medical University |
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Principal Investigator |
SAIHO Ko Nara Medical University, Surgeryl, Research Assosiate, 医学部・第1外科, 助手 (80305713)
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| Co-Investigator(Kenkyū-buntansha) |
KANEHIRO Hiromich Nara Medical University, Surgeryl, Research Assosiate, 医学部・第1外科, 助教授 (30204580)
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| Project Period (FY) |
1999 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2001: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2000: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1999: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | peripheral blood stem cell / organ transplantation / tolerance / bone marrow transplantation / Small bowel transplantation / hepatocellular carcinoma / CD45 / chimerism |
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| Research Abstract |
We tried to induce donor-specific immune tolerance using donor-derived hematopoietic cells and bone marrow chimerism, which may lead to clonal deletion. G-CSF mobilized peripheral blood hematopoietic stem cells have reduced costimulatory function, which may induce anergy of allergenic T cells. Allergenic donor-derived hematopoietic stem cells could not be accepted ithout preconditioning of the recipient, even after modification with hematopoietic cytokines. Then preconditioning regimens using cyclophosphamide (CYP) monotherapy were evaluated. High dose CYP induced stable hematopoietic chimerism, but the recipient developed severe GVHD. Modification of donor-derived hematopoietic stem cells with various kinds of cytokines resulted in long-lasting bone marrow chimerism by non-lethal dose of CYP preconditioning. GVHD was avoided with this modification. Chimeric recipients accepted heart allograft from bone marrow donor strain without immunosuppression. Preconditioning with anti-CD45 monoclonal antibody (mAb) also induced hematopoietic chimerism. The anti-CD45 mAb enhanced donor-derived passenger leukocytes and induced heart allograft acceptance. We also focused on characteristic feature of small bowel allograft which have abundant donor-derived lymphocytes in the mesenteric lymph nodes (MLNs). Significance of immune interaction between donor and recipient lymphocytes in the garft MLNs was shown. Modification of costimulatory function of donor-derived spleen cells resulted in donor-specific immunosuppression. The immunosuppressive effect of composite liver allograft, which contained a lot of donor-derived passenger leukocytes, was also shown in a rat liver/small bowel allograft model. Tolerance induction is beneficial especially for patients with malignant tumor, because immunosuppression may promote tumor progression. Then we studied indication of liver transplantation for patients with hepatocellular carcinoma.
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