1994 Fiscal Year Final Research Report Summary
Development of Gene Therapy for Type I Diabetes Using Cytokine Gene and Pancreatic Islet B Cell-Specific Lymphocytes
| Project/Area Number |
04557132
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| Research Category |
Grant-in-Aid for Developmental Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
内分泌・代謝学
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| Research Institution | The University of Tokishima |
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Principal Investigator |
ITAKURA Mitsuo The University of Tokushima, Sch.Med., Prof., 医学部, 教授 (60134227)
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| Co-Investigator(Kenkyū-buntansha) |
KAMOGASHIRA Takashi Otsuka Pharmaceutical Company, Cellular Technology Research Center, 細胞工学研究所
KOKAI Yasuo The National Children's Research Center
MIYAZAKI Junichi The University of Tokyo, Faculty of Medicine, Prof., 医学部, 教授 (10200156)
IWAHANA Hiroyuki The University of Tokushima, Sch.Med., Assistant, 医学部, 助手
YOSHIMOTO Katsuhiko The University of Tokushima, Sch.Med., Assoc.Prof., 医学部, 助教授 (90201863)
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| Project Period (FY) |
1992 – 1994
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| Keywords | gene therapy / pancreatic islet B-cell / deabetes / IDDM / cytokine / IL-10 / lymphocytes / paracrine secretion |
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| Research Abstract |
Interleukin 10 (IL-10) can either suppress or aggravate insulin-dependent diabetes mellitis(IDDM). The suppression is possible based on the fact that IL-10 strongly inhibits IFN-gamma synthesis from macrophages or Th1 lymphocytes. The aggravation is expected based on a fact that IL-10 induces MHC Class II molecules, and another observation that cytotoxic lymphocytes secretes IL-10 and IFN-gamma concomitantly. To elucidate the role of IL-10 in situ in the pancreatic islets during the immunological destruction process, we first produced transgenic mice (Tg) in the NOD strain(NOD-IL-10-Tg). By fusing rat glucagon promoter with mouse IL-10 cDNA,the production of IL-10 in this Tg model is rendered to be localized in pancreatic islet A cells. The produced IL-10 is expected to exhibit its function by the paracrine mechanism toward pancreatic islet B cells. The advantage of this system is that pancreatic islet B cells are not molecularly modified. NOD-IL-10-Tg exhibited severe insulitis and ductal proliferation with fibrosis around the islets. They became diabetic even before the age of 10 weeks. The second approach was to use the pancreatic islet B cell-specific lymphocytes. By using 4 lymphocyte clones isloted from pancreatic infiltrates in NOD mice, the possibility of delivering IL-10 to the very locus of insulitis was examined. In the adoptive transfer model, diabetes was transferred to young NOD mice by these lyphocyte cell lines. By adoptively transferring lymphocyte cell lines which were transduced with IL-10 cDNA,the incidence of transferred diabetes was significantly reduced. In addition, adoptive transfer of the mixture of wild type lymphocytes with transduced lymphocytes showed the strong suppression of the occurrence of diabetes in this model. This study showed the various functions of IL-10, but it supplied the theoretical basis for the development of gene therapy for diabetes with lymphocytes transduced with IL-10.
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