| Project/Area Number |
15591346
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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 | Yamaguchi University |
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Principal Investigator |
NOSHIMA Shinji Yamaguchi University, Faculty of Medicine, Associate Professor, 医学部, 助教授 (40243654)
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| Co-Investigator(Kenkyū-buntansha) |
HAMANO Kimikazu Yamaguchi University, Faculty of Medicine, Professor, 医学部, 教授 (60263787)
ITO Hiroshi Yamaguchi University, Hospital, Research Associate, 医学部附属病院, 助手 (90363100)
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2005: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2004: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2003: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Keywords | small bowel transplantation / tolerance / mixed chimerism / マウス / costimulatory blockade / 移植免疫 |
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| Research Abstract |
Aims : Mixed chimerism is known as one of the most powerful method to induce donor specific tolerance. Here we evaluate the potential advantage of mixed chimerism with costimulatory blockade in murine allogeneic small bowel transplantation.
Methods : C57BL/6 received various combination of anti-CD8(2.43;1.4mg, day -2) and anti-CD154(MRI ; 2mg, day -1)mAbs with/without 3Gy total body irradiation (TBI, day -1), and 20×10^6 fully MHC-mismatched B10. A bone marrow cells (BMC, day -1). Heterotopic small bowel transplantation was performed on day 0 to assess induction of donor specific tolerance. Chimerism in peripheral blood was followed by FCM analysis and the frequency of TCR Vβ usage was determined by FCM to assess deletion of donor-reactive T cells. Stoma was daily observed, and acute rejection was evaluated with a microscope.
Results : All animals without any treatment (n=6) showed acute rejection within 18 days after transplantation, and microscope examination presented the findings of
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acute rejection such as flattend villous epithelium with the infiltration of inflammatory cells. Mice receiving anti-CD8 and anti-CD154 mAbs (n=10) were not induced mixed chimerism, and showed marked prolongation of small bowel allograft, butrejected within 100 days. Mice treated with anti-CD8mAb,anti-CD154,TBI, and BMC(n=11) was induced permanent multi-lineage mixed chimerism and accepted small bowel allografts (>300 days). Microscope examination presented the no findings of rejection. These chimeric animals showed specific deletion of donor reactive CD4^+ peripheral blood lymphocytes (Vβ5 and Vβ11 cells). Skin grafting was performed 300 days after small bowel transplantation to examine whether tolerance was induced or not. Mice that accepted donor small bowel permanently also accepted donor B10. A skin graft, however, 3rd party B10. BR skin were rejected rapidly after grafting.
Conclusions : Small bowel transplantation tolerance was achieved using mixed chimerism with costimulatory blockade. Mixed chimerism is the essential and reliable regimen toward to the small bowel transplantation. Less
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