| Project/Area Number |
63570597
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
General surgery
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| Research Institution | Osaka University |
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Principal Investigator |
GOTOH Mitsukazu Osaka University Medical School, 2nd Department of Surgery, Medical school assistant, 医学部, 助手 (50162160)
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| Co-Investigator(Kenkyū-buntansha) |
KAWAI Minoru Osaka University Hospital, 2nd Department of Surgery, Surgical staff, 医学部附属病院, 医員
KANAI Toshio Osaka University Medical School, 2nd Department of Surgery, Medical school assis, 医学部, 助手 (50205051)
MONDEN Morito Osaka University Medical School, 2nd Department of Surgery, Medical school lectu, 医学部, 講師 (00127309)
山本 仁 大阪大学, 医学部附属病院, 医員
久保田 直行 大阪大学, 医学部附属病院, 医員
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| Project Period (FY) |
1988 – 1989
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| Project Status |
Completed (Fiscal Year 1989)
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| Budget Amount *help |
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 1989: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1988: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Keywords | Islet transplantation / Antigen modulation / gamma-irradiation / Anti-lymphocyte serum / Immunomodulation / Islet transplantation / Antigen modulation / γーirradiation / AntiーLymphocyte serum / MHC class II / ラ氏島移植 / 再構築ラ氏島 / antigen-modulation |
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| Research Abstract |
In pancreatic islet transplantation, the immunogenicity of the graft can be easily modulated by using methods such as simple purification by handpicking, UV irradiation, anti-Ia antibody and complement treatment and in vitro culture. If the immunogenicity of islets can be reduced enough to prevent the immunological response to the graft, the allogeneic islets may be accepted by recipient without immunosuppression. In this study, we aimed at complete reduction of the islet immunogenicity, and tried to develop the methods for effective immmunomodulation of the graft.
First, we examined the effect of anti-lymphocyte serum (ALS) on mouse islet allograft survival. DBA/2 islet allografts transplanted beneath the nonimmunosuppressed B6AF1 renal subcapsular space were acutely rejected within 18 days. In contrast, the islets transplanted into ALS-treated recipients survived for more than 200 days. The timing of ALS administration to the recipient is crucial in producing indefinite survival of is
… More
let allografts. ALS given at the time of islet grafting produced maximal islet survival. ALS treatment of recipient mice on day -2 and day +2 had less effect on islet survival. Transplantation of islets from ALS-treated donors (day -5 and day -2:ip) into ALS-treated recipients (day -2) caused indefinite graft survival. These results indicate that ALS has not only an immunosuppressive effect on the recipients. but also the capacity to modify the immunogenicity of the crude islet allografts.
Second, we examined the effect of gamma-irradiation on mouse islet-allograft survival. Crude B6AF_1 islets were irradiated at varying doses and transplanted into syngeneic recipients for determination of possible induction of irradiation injury. The islet isografts irradiated with 2400 rad survived >200 days postgaft. When islets were irradiated >4000 rad, most isograft recipients became hyperglycemic within 200 days. Islets irradiated with 16000 rad falled to restore normglycemia. The capacity of gamma-irradiation to reduce immunogenicity of islets was examined by transplanting irradiated DBA/2 islets into B6AF_1 mice. Eight out of 16 islet allografts which were irradiated with 2400 rad survived > 50 days, while all non-irradiated islet allografts were acutely rejected. Moreover, administration of CsA at 100mg/kg/2 days for 2 wk resulted in significant prolongation of graft survival, with 10 of 11 allografts surviving >100 days. gamma-irradiation has a potential capacity to reduce the immunogenicity of islet allograft without deterioration of islet function.
In this study we used crude digested islets, which contained highly immunogenic contaminants such as lymphnodes. Thus, these methods may serve as simple and effective modalities to reduce graft immunogenicity in human pancreatic islet transplantation. Less
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