PATHOGENESIS AND PREVENTION OF TYPE I DIABETES IN THE NOD MOUSE AND MAN

本应用程序的中心目标是了解自我 反应性T细胞在非肥胖糖尿病（NOD）小鼠疾病期间产生 进展有人认为，胰岛炎和随后的糖尿病 由自身反应性T细胞的免疫调节失衡引起， 作为Th 1对Th 2 T细胞亚群功能和细胞因子的优势， 生产然而，目前的工作所缺乏的是 在体内跟随抗原特异性T细胞应答的能力， 疾病进展。为了验证这一假设，并确定 这种耐受性丧失的潜在机制，我们建议使用肽/MHC 已经开发了多聚体以在抗原特异性免疫反应中染色T细胞， 跟踪T细胞对两种β细胞抗原-GAD（谷氨酸）应答的方式 脱羧酶）和胰岛素。尽管 GAD和胰岛素特异性的发展中的可察觉的差异 T细胞。这两项提议都是为了标志着一个关键的转折点， NOD小鼠中的IDDM的发展。此外，无论是GAD耐受 或胰岛素在糖尿病前期小鼠中大大降低了疾病的发生率。 因此，通过在疾病进展之前和期间跟踪这些T细胞， 在治疗干预之后，我们希望实现以下目标 目标：（i）记录这些自身反应性T细胞何时发育以及在何处发育。 （二）确定是否有变更; 细胞因子对抗原的反应，如果是这样，变化是什么，什么时候 它们是否发生;（iii）这些T细胞的特征是什么 当NOD小鼠耐受这些蛋白质时。 NOD患者自身反应性T细胞的发展 小鼠将为T细胞介导的自体免疫提供重要的新见解。 免疫力发展。这些信息可以用于开发和测试 治疗干预方案。

The central objective of this application is to understand how self reactive T cells develop in non obese diabetic (NOD) mice during disease progression. It has been suggested that insulitis and subsequent diabetes is induced by an immunoregulatory imbalance of autoreactive T cells, such as a dominance of Th1 over Th2 T-cell subset function and cytokine production. However, what has been lacking in the current work is the ability to follow an antigen specific T cell response in vivo as the disease progresses. In order to test this hypothesis, and determine the mechanism underlying this loss of tolerance, we propose to use peptide/MHC multimers which have been developed to stain T cells in antigen specific manner to follow T cell responses to two beta cell antigens-GAD (glutamate decarboxylase) and insulin in vivo as the disease progresses. In spite of the perceptible differences in the development of GAD and insulin specific T cells. both have been proposed to mark a key turning point in the development of IDDM in NOD mice. In addition, tolerization with either GAD or insulin in pre diabetic mice greatly reduces the incidence of disease. Thus, by tracking these T cells before and during disease progression, and following therapeutic intervention, we hope to achieve the following goals: (i) document when these auto-reactive T cells develop and where they reside; (ii) determine whether or not there is a change in their cytokine responses to antigens, and if so, what are the changes and when do they occur; and (iii) what are the characteristics of these T cells when NOD mice are tolerized with these proteins. A clear understanding of the development of self-reactive T cells in NOD mice will provide important new insights into how a T cell mediated auto- immunity develops. Such information can then be used to develop and test protocols for therapeutic interventions.