ROLE OF CD8 T CELLS IN INITIATION OF AUTOIMMUNE DIABETES

这个项目的总体目标是探索T和B的作用 淋巴细胞在酒精性糖尿病发病机制及预防中的作用 老鼠。基本上，我们之前的研究表明，IDDM在NOD 小鼠是由于自身侵袭性T细胞之间的平衡发生变化而导致的 以及调节其活动或更好地呈现其效应器动作的细胞 细胞。本项目将探索CD8 T细胞在人类免疫缺陷中的作用。 糖尿病进程的启动。我们分离并克隆了CD8 T细胞 这些小鼠早期出现的细胞；CD8T细胞在2-4岁时耗尽 众所周知，几周可以预防糖尿病。使用这些克隆的T细胞，我们 计划实现以下具体目标：1.准备好会展 转基因T细胞受体，为了研究它们的成熟度， 激活和效应器功能。2.我们将鉴定它们的β细胞 使用为灵敏检测而设计的杂交物的特定抗原 编码抗原肽的CDA。我们将确定 这些细胞归巢到胰岛的机制，这发生在 第一次注射后三个小时。4.我们认为CD4T细胞是 只有当CD8细胞释放自身抗原时才被激活，我们 我相信B细胞在发生的多样化中起着关键作用 在这件事之后。这是因为缺乏β基因的NOD小鼠不会 患上糖尿病。我们将通过以下方式探讨β细胞在糖尿病中的作用 使用缺乏β细胞的NOD小鼠或通过阻断CD40配体 这是赋予这些细胞协同刺激活动所必需的 细胞。最终，我们希望我们的分析将提供线索， 允许我们通过注射胰岛素来预防糖尿病，因为我们 有证据表明胰岛素特异性T细胞可以阻止领养 在我们的小鼠身上转移和自发性疾病。

The overall goal of this project is to explore the role of T and B lymphocytes in the pathogenesis and prevention of IDDM in NOD mice. Basically, our prior studies have shown that IDDm in NOD mice results from shifts in the balance between autoaggressive T cells and cells that regulate their activity or present their effector action bet cells. This project will explore the role of CD8 T cells in the initiation of the diabetic process. We have isolated and cloned CD8 T cells that appear early in these mice; depletion of CD8 T cells at 2-4 weeks is known to prevent diabetes. Using these cloned T cells, we plan to pursue the following specific aims: 1. We will prepare mice transgenic for the T cell receptor, in order to study their maturation, activation, and effector functions. 2. We will identify their beta cell specific antigen using hybrids engineered for sensitive detection of cDA encoding the antigenic peptide. We will determine the mechanism of homing of these cells to the islets, which happens in the first three hours after injection. 4. We believe that CD4 T cells are only activated once the CD8 cells have released autoantigens, and we believe that B cells play a critical role in the diversification that occur after this event. This is because beta-deficient NOD mice do not develop diabetes. We will explore the role of beta cells in diabetes by using NOD mice lacking beta cells or by blocking the CD40 ligand which is necessary for conferring co-stimulatory activity on these cells. Eventually, we hope our analysis will provide clues that will allow us to prevent diabetes using insulin using insulin injection, as we have evidence that an insulin-specific T cell can block adoptive transfer and spontaneous disease in our mice.