TH1, TH2 CELLS IN INSULIN DEPENDENT DIABETES MELLITUS

我们建议研究β细胞反应性Th1和 Th2 T细胞与胰岛素依赖型糖尿病的发生发展 点头老鼠。我们的建议是基于以下先前的观察结果；i) 我们制作了一只携带重排T细胞受体的转基因NOD小鼠 (TCR)来自糖尿病和β细胞特异性的CD4+T细胞；ii)该TCR 在转基因NOD小鼠的T细胞上表达，而这些细胞不是 对β细胞抗原的耐受性；iii)未被操纵的TCR转基因 在4个月大时患上迅速而严重的胰岛素炎并患上糖尿病； IV)当这些T细胞重新产生Th1和Th2T细胞系时 转移到新生的NOD小鼠中，只有Th1细胞可以传播疾病 而Th2 T细胞尽管携带相同的TCR和 渗入胰岛。因为在我们的TCR转基因小鼠中 有了抗原和TCR的特异性和亲和力的变量，我们就可以 结论Th1T细胞是相应的抗原特异性效应细胞 而且Th2细胞是良性的。 这一建议旨在测试这一假设是否适用于 IDDM的自发发展，如果是这样的话，我们是否可以开发出钝化的方法 持续的破坏性Th1领导的对良性TH2的反胰岛反应。我们 建议这样做如下： 1)测试我们的TCR转基因小鼠是否被剥夺了某些战略 Th1或Th2类淋巴因子可发展为IDDM。这将通过培育我们的 对淋巴因子或淋巴因子受体基因敲除突变小鼠的TCR 到过度表达调节性淋巴因子的小鼠。 2)测试调节性T细胞在抑制 促糖尿病Th1T细胞的活性。这将由任何一个人完成 将我们的转基因T细胞引入完全没有或 富含在其他淋巴样细胞中。 3)探讨Th2细胞对T细胞的潜在调节作用。 控制IDDM并寻找Th1T细胞向Th2细胞转移的方法 在持续疾病中的表型。

We propose to examine the relationship between beta cell-reactive Th1 and Th2 T cells an th e development of insulin-dependent diabetes mellitus of NOD mice. Our proposal is based on the following previous observations; i) we made a transgenic NOD mouse carrying the rearranged T cell receptors (TCR) from a diabetogenic and beta cell-specific CD4+ T cell; ii) this TCR is expressed on the T cells in transgenic NOD mice, and these cells are not tolerant to the beta cell antigen; iii) the un-manipulated TCR transgenics develop a rapid and severe insulitis and falls diabetic at 4 months of age; iv) when Th1 and Th2 T cell lines re generated from these T cells and transferred in to neonatal NOD mice, only the Th1 line can transfer disease while the Th2 T cells don't despite carrying the identical TCR and infiltrating the pancreatic islets. Since in our TCR transgenic mice we have fix the variables o antigen and TCR specificity and affinity, we can conclude that Th1 T cells are the relevant antigen specific effector cell in diabetes and that Th2 cells are benign. This proposal is designed to test whether this hypothesis holds true in the spontaneous development of IDDM, and if so, can we develop methods to blunt an ongoing destructive Th1-led anti-islet response to a benign TH2. We propose to do this as follows: 1) To test whether our TCR transgenic mice deprived of certain strategic Th1 or Th2 lymphokines can develop IDDM. This will be done by breeding our TCR to mice with lymphokine or lymphokine receptor knock-out-mutations or to mice which over-express regulatory lymphokines. 2) To test the role of regulatory T cells may play in dampening the activity of diabetogenic Th1 T cells. This will be done by either introducing our transgenic T cells into environments completely devoid or enriched in other lymphoid cells. 3) To investigate the potential regulatory effects of Th2 cells on the control of IDDM and to find the means of diverting Th1 T cells to a Th2 phenotype in ongoing disease.