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

这个应用程序的中心目标是了解如何自我 非肥胖糖尿病(NOD)小鼠发病过程中反应性T细胞的发育 进步。已有研究表明，胰岛炎症和随后的糖尿病 是由自身反应性T细胞的免疫调节失衡引起的，如 作为Th1对Th2 T细胞亚群功能和细胞因子的优势 制作。然而，目前的工作所欠缺的是 在体内跟踪抗原特异性T细胞反应的能力 疾病就会发展。为了检验这一假设，并确定 这种耐受性丧失的机制，我们建议使用多肽/MHC 已开发的用于抗原特异性T细胞染色的多聚体 跟踪T细胞对两种β细胞抗原-GAD(谷氨酸)反应的方式 脱羧酶)和体内的胰岛素，随着疾病的进展。尽管 广泛性焦虑症和胰岛素特异症发生过程中的明显差异 T细胞。这两个提议都是为了标志着 NOD小鼠IDDM的发生发展。此外，对任一GAD的容忍度 糖尿病前期小鼠体内的胰岛素可以极大地降低疾病的发病率。 因此，通过在疾病进展之前和期间跟踪这些T细胞，以及 在治疗性干预之后，我们希望实现以下目标 目标：(I)记录这些自身反应性T细胞何时何地发育 他们居住；。(Ii)决定他们的 细胞因子对抗原的反应，如果是，变化是什么，什么时候 它们是否发生；以及(Iii)这些T细胞有什么特征 当NOD小鼠对这些蛋白质耐受时。 对NOD中自身反应性T细胞发育的清晰认识 小鼠将为T细胞如何介导自身免疫反应提供重要的新见解。 免疫力就会增强。然后可以使用这些信息来开发和测试 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.