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发挥不同的功能。在I型胰岛素依赖型糖尿病(IDDM)中，免疫细胞(包括Th0、Th1和Th2淋巴细胞)和细胞因子(包括干扰素-γ)是IDDM自身免疫过程的病因。IL-10是已知的细胞因子合成抑制因子(CSIF)，它抑制干扰素-γ的合成。另一方面，IL-10的炎症功能与黏附分子的MHC-II类分子表达增加有关。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，我们培育了两种不同的转基因小鼠，其中细胞因子的合成针对胰岛A细胞。该策略是这样的，在胰岛A细胞中产生各种细胞因子，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细胞根本不是分子修饰的。第一个转基因小鼠(TG)是在BDF1品系中产生的，只有在没有IE的遗传背景下才表现出对糖耐量受损的胰岛的淋巴细胞浸润；第二个TG是NOD品系产生的NOD-IL-10-TG，雄性和雌性创始小鼠甚至在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炎症和导管增生，并伴有胰腺纤维化。这些转基因小鼠清楚地表明，各种细胞因子的局部传递可以强烈地改变IDDM的自然病程。本研究为开发针对自身免疫性胰腺炎的免疫抑制细胞因子基因治疗提供了新的基础。

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.