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具有不同的功能。在I型胰岛素依赖型糖尿病（insulin dependent diabetes，IDDM）中，Th 0、Th 1、Th 2等免疫细胞和IFN-γ等细胞因子参与了自身免疫过程，IL-10是一种细胞因子合成抑制因子（cytokine synthesis inhibitory factor，CSIF），它抑制IFN-γ的合成。另一方面，IL-10的炎性功能已被报道为增加粘附分子的MHC II类分子的表达。为了研究细胞因子对胰岛B细胞的免疫破坏的局部原位作用，我们产生了两种不同的转基因小鼠，其中细胞因子合成靶向胰岛A细胞。该策略使得胰岛A细胞中各种细胞因子的产生通过旁分泌机制向胰岛B细胞提供细胞因子。该策略在胰腺胰岛B细胞根本没有分子修饰的意义上是有利的。第一个转基因小鼠（Tg），IFN-γ Tg产生于BDF 1品系，仅在缺乏IE的遗传背景下表现出淋巴细胞浸润到胰岛的糖耐量受损，第二个转基因小鼠（Tg），NOD-IL-10-Tg产生于NOD品系，在10周龄之前雄性和雌性创始小鼠均表现出严重的糖尿病。他们表现出严重的胰岛炎和胰腺导管增生伴纤维化。这些转基因小鼠清楚地表明，胰岛素依赖型糖尿病的自然病程可以通过局部递送各种细胞因子来强烈改变。本研究为将免疫抑制细胞因子靶向自身免疫性胰岛炎提供了新的基因治疗方法。

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.