Analysis of Immunological Destruction Mechanism of Pancreatic Islet B Cells Using a Transgenic Mouse Model

细胞因子在不同的靶细胞中表现出不同的功能。在I型胰岛素依赖型糖尿病（IDDM）中，包括Th0、Th1和Th2淋巴细胞在内的免疫细胞和包括ifn - γ在内的细胞因子是IDDM免疫过程的病因。IL-10被称为细胞因子合成抑制因子（CSIF），它抑制ifn - γ的合成。另一方面，IL-10的炎症功能已被报道为粘附分子中MHC II类分子的表达增加。为了研究细胞因子在胰岛B细胞免疫破坏中的局部原位作用，我们生产了两只不同的转基因小鼠，其中细胞因子的合成是针对胰岛A细胞的。胰岛A细胞产生的各种细胞因子通过旁分泌机制向胰岛B细胞提供细胞因子。这种策略是有利的，因为胰岛B细胞根本没有分子修饰。第一个转基因小鼠（Tg）， ifn - γ Tg在BDF1菌株中产生，仅在没有IE的遗传背景下，它表现出对糖耐量受损的胰岛的淋巴细胞浸润。NOD品系产生第二种Tg， NOD- il -10-Tg，在雄性和雌性创始小鼠中，它甚至在10周龄之前就表现出严重的糖尿病。他们表现出严重的胰岛素炎和胰腺导管增生伴纤维化。这些转基因小鼠清楚地表明，多种细胞因子的局部递送可以强烈地改变IDDM的自然过程。本研究为开发新的基因治疗IDDM提供了基础，通过将免疫抑制细胞因子传递到自身免疫性胰岛素的位点。

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.