| Project/Area Number |
07407033
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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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 | Osaka University |
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Principal Investigator |
MONDEN Morito OSAKA University Medical School, Professor, 医学部, 教授 (00127309)
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| Co-Investigator(Kenkyū-buntansha) |
MIYOSHI Hideyuki OSAKA University Medical School Hospital, Medical Staff, 医学部・付属病院, 医員
OHZATO Hiroki OSAKA University Medical School, Assistant Professor, 医学部, 助手 (10273682)
DONO Keizo OSAKA University Medical School, Assistant Professor, 医学部, 助手 (60283769)
UMESHITA Koji OSAKA University Medical School, Assistant Professor, 医学部, 助手 (60252649)
GTOH Mitsukazu OSAKA University Medical School, Associate Professor, 医学部, 助教授 (50162160)
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| Project Period (FY) |
1995 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥33,500,000 (Direct Cost: ¥33,500,000)
Fiscal Year 1997: ¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 1996: ¥10,600,000 (Direct Cost: ¥10,600,000)
Fiscal Year 1995: ¥20,300,000 (Direct Cost: ¥20,300,000)
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| Keywords | Rat heart transplantation / Rat liver transplantation / Donor antigen transplantation / Tolerance induction / microchimerism / Thymus / 門脈寛容 / マイクロキメリズム / サイトカイン / Th1 / Th2 / 心移植 / マイトマイシン / 抗原特異的免疫不応答 / 接着分子 / 肝移植 / 膵島移植 |
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| Research Abstract |
In this study, we tried to establish a method for donor specific tolerance induction applicable to clinical organ transplantation. In the first set of experiments, we examined the effect of immuno-modulation of donor tissue and transient immunosuppresion of recipients on graft acceptance. We observed significant prolongation of heart graft survival with pretransplant inoculation of donor SPCs treated with Mytomycin C (MMC). MMC treatment down-regulated ICAM-1 expression thus lead decreased co-stimulatory signal through adhesion molecules. In the second experiment, we examined the effect of blockage of LFA-1/ICAM-1 co-stimulatory signal using anti-LFA-1 Ab in mouse islet transplantation model. Donor specific tolerance was induced in the mice treated with anti-LFA-1 Ab. Combined anti-LFA-1/ICAM-1Ab treatment also prolonged xeno islet graft survival in rat to mouse model. It was clearly shown that blockage of co-stimulatory signal leaded donor specific tolerance in allogeneic combination
… More
and prolonged islet survival in xeno combination. In the third experiment, we examined the combination of the both treatments. Rat islets were pretreated with MMC and were transplanted to anti-LFA-1/ICAM-1Ab treated diabetic mice. Almost all the recipients were accepted xenogeneic islets over 100 days, and they also accepted the second grafts from the same donor strain. We concluded that immuno-moldulation of the donor antigen and blockage of co-stimulatory signal can induce donor specific tolerance. In the second set of experiment, we analyzed microchimerism of donor originated cells in blood, spleen, liver and especially in the thymus after rat heart transplantation. Specific disappearance of donor cells in the thymus before graft rejection. Thymectomized rat recipients rejected liver allograft earlier than naive recipients. Thus we concluded that microchimerism of donor cells in the thymus is very important for graft acceptance. Finally we tried a new approach using apoptosis of attacking T cells via Fas/FasL system. Mouse islets were transplanted under the kidney subcapsule as a composite graft with testicular tissue, which is known as a FasL rich tissue. Graft survival was prolonged in the recipient mice transplanted the composite graft. TUNEL staining showed apoptotic death of the infiltrating lymphocytes. We assumed that graft acceptance was achieved by killing of infiltrating T cells through apoptotic pathway originated FasL stimulation from testicular tissue. We are now trying to make the islet cells express FasL using transgene technology. Less
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