TH1, TH2 CELLS IN INSULIN DEPENDENT DIABETES MELLITUS

我们建议检查β细胞反应性Th 1和 Th 2 T细胞与胰岛素依赖型糖尿病的发生 NOD小鼠。 我们的建议是基于以下先前的意见： 我们制造了一只携带重排T细胞受体的转基因NOD小鼠 (TCR)来自致糖尿病和β细胞特异性CD 4 + 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细胞抗原耐受; iii）未操作的TCR转基因 在4个月大时发生快速和严重的胰岛炎并患上福尔斯糖尿病; iv）当Th 1和Th 2 T细胞系从这些T细胞重新产生时， 转移到新生NOD小鼠中，只有Th 1细胞系可以转移疾病 而Th 2 T细胞尽管携带相同的TCR， 浸润了胰岛 因为在我们的TCR转基因小鼠中， 确定了抗原和TCR特异性和亲和力的变量，我们可以 结论Th 1 T细胞是相关的抗原特异性效应细胞 Th 2细胞是良性的。 这一提议旨在检验这一假设是否适用于 自发发展的胰岛素依赖型糖尿病，如果是这样，我们可以开发的方法， 一个持续的破坏性Th 1-主导的抗胰岛反应良性TH 2。 我们 建议采取以下行动： 1)为了测试我们的TCR转基因小鼠是否被剥夺了某些战略性的 Th 1或Th 2淋巴因子可发展为IDDM。 这将通过繁殖我们的 TCR对具有淋巴因子或淋巴因子受体敲除突变的小鼠，或 过度表达调节性淋巴因子的小鼠。 2)为了测试调节性T细胞在抑制免疫反应中的作用， 致糖尿病Th 1 T细胞的活性。 这将由以下两种方式完成： 将我们的转基因T细胞引入完全缺乏或 富含其他淋巴细胞。 3)为了研究Th 2细胞对免疫功能的潜在调节作用， 控制胰岛素依赖型糖尿病，并找到将Th 1 T细胞转向Th 2 T细胞的方法。 正在进行的疾病的表型。

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.