| Project/Area Number |
10671081
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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 |
Metabolomics
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| Research Institution | Saitama Medical University Department of Medicine |
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Principal Investigator |
KATAYAMA Shigehiro Saitama Medical School, Department of Medicine Professor, 医学部, 教授 (90167338)
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| Co-Investigator(Kenkyū-buntansha) |
TAKEI Shinichiro Saitama Medical School, Department of Medicine Assistant, 医学部, 助手 (30286067)
NEGISHI Kiyohiko Saitama Medical School, Department of Medicine Associate Professor, 医学部, 助教授 (00180696)
IITAKA Makoto Saitama Medical School, Department of Medicine Associate Professor, 医学部, 助教授 (10142407)
KOMEDA Kajuro Tokyo Medical University, Department of Medicine, Associate Professor, 医学部, 助教授 (90074533)
HAMADA Hirofumi Sapporo Medical University, Department of Medicine, Professor, 癌科学療法センター, 分子生物治療研究部長 (00189614)
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| Project Period (FY) |
1998 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2000: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1999: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1998: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | CTLA4Ig / diabetes mellitus / gene therapy / BB / W / TKY rat / アデノウィルス |
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| Research Abstract |
We tested if rat islets that were engineered to produce human CTLA4Ig locally at the graft site could survive and prevent the onset of diabetes mellitus in BB/W//TKY rats, an animal model of human type 1 diabetes. CTLA4Ig, a soluble fusion protein of human CTLA-4 and the immunoglubulin G1 Fc region, binds to human and murine CD80/CD86 with high avidity and blocks T cell activation in vitro.
Islets obtained from 8〜10 week-old nondiabetic BB/W//TKY rats were transfected with recombinant adenovirus vectors to express CTLA4Ig. After transfection, 1000 islets transfected with Adex1CACTLA4Ig were transplanted under the renal capsule or in the muscles of a nondiabetic 8 week-old BB/W//TKY rats. Antibodies to rat LFA-1 and to rat ICAM-1 (200 μg/rat) were also given ip to the rats on the day before transplantation and on 1, 3, and 5 days after transplantation. BB/W//TKY rats spontaneously developed diabetes by the age of 12 weeks. Administration of antibodies to rat LFA-1 and to rat ICAM-1 could
… More
not prevent the onset of diabetes. When islets producing CTLA4Ig were transplanted under the renal capsule with antibodies, 3 rats developed diabetes by 12 week-old ; 3 developed diabetes by 14 week-old ; 3 kept normoglycemia at least by 30 week-old. When islets were transplanted in the muscles of the lower leg together with antibodies, all rats (n=3) developed diabetes by 12 week-old.
Islets obtained from Wistar rats and transfected with Adex1CACTLA4Ig were also transplanted under the renal capsule of 4 streptozotocin-treated diabetic SD rats. Antibodies to rat LFA-1 and to rat ICAM-1 were also given ip. Blood glucose levels in 2 transplanted rats were kept normal for more than 30 days after transplantation, although those of remaining 2 rats elevated 10 days and 25 days after transplantation.
These observations indicate that interference with costimulatory signal by CTLA4Ig-producing islets and antibodies to LFA-1 and ICAM-1 can prevent autoimmune destruction of islet cells and rejection of the grafts. This would be a useful therapeutic strategy for human islet transplantation. Less
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