1994 Fiscal Year Final Research Report Summary
Analysis of Immunological Destruction Mechanism of Pancreatic Islet B Cells Using a Transgenic Mouse Model
| Project/Area Number |
05454323
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| Research Category |
Grant-in-Aid for General 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 Tokushima |
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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) |
MIYAZAKI Junichi The University of Tokyo, Faculty of Medicine, Prof., 医学部, 教授 (10200156)
HIMENO Kunisuki The University of Tokushima, Sch.Med., Prof., 医学部, 教授 (50112339)
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) |
1993 – 1994
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| Keywords | gene therapy / pancreatic islet B-cell / diabetes / IDDM / cytokine / IL-10 / lymphocytes / paracrine secretion |
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| Research Abstract |
Cytokine exhibits various functions in various target cells. In type I insulin-dependent diabetes (IDDM) , immunocytes including Th0, Th1, and Th2 lymphocytes and cytokines including IFN-gamma are etiologic for the autommune process of IDDM.IL-10 is known as a cytokine synthesis inhibitory factor (CSIF) and it inhibits IFN-gamma synthesis. On the other hand, inflammatory functions of IL-10 have been reported in regard to the increased expression of MHC Class II molecules of adhesion molecules. To examine the local in situ role of cytokines for the immunological destruction of pancreatic islet B cells, we produced two different transgenic mice in which cytokine synthesis is targetted to pancreatic islet A cells. The strategy is such that the production of various cytokines in pancreatic islet A cells supplies cytokines to pancreatic islet B cells via a paracrine mechanism. This strategy is advantageous in the sense that the panceatic islet B cells are not molecularly modified at all. The first transgenic mouse (Tg) , IFN-gamma Tg was produced in BDF1 strain, and it exhibited lymphocytic infilatration to pancreatic islets with impaired glucose tolerance only in the genetic background of the absence of IE.The second Tg, NOD-IL-10-Tg was produced in NOD strain, and it exhibited severe diabetes even before 10 weeks of age both in male and female founder mice. They showed severe insulitis and ductal proliferation with fibrosis in the pancreas. Theses transgenic mice clearly showed that the natural course of IDDM can be strongly modified by the local delivery of various cytokines. This study affords the basis to develop new gene therapy of IDDM by delivering immunosuppressive cytokines to the very locus of the autoimmune insulitis.
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