ROLE OF CD8 T CELLS IN INITIATION OF AUTOIMMUNE DIABETES

CD8 T 细胞在引发自身免疫性糖尿病中的作用

• 批准号: 6105804
• 负责人: CHARLES A JANEWAY
• 金额: $ 17.62万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6105804
• 关键词: B lymphocyte; CD4 molecule; CD40 molecule; CD8 molecule; T lymphocyte; autoantigens; cell migration; disease /disorder etiology; disease /disorder model; gene expression; genetic manipulation; genetically modified animals; helper T lymphocyte; immunocytochemistry; insulin dependent diabetes mellitus; laboratory mouse; model design /development; molecular cloning; pancreatic islets; pathologic process; suppressor T lymphocyte

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.

该项目的总体目标是探索T和B的作用 淋巴细胞在 NOD IDDM 发病机制和预防中的作用 老鼠。 基本上，我们之前的研究表明，NOD 中的 IDDm 小鼠由于自身攻击性 T 细胞之间的平衡发生变化而产生 以及调节其活动或呈现其效应器作用赌注的细胞 细胞。 该项目将探讨 CD8 T 细胞在 糖尿病过程的开始。 我们分离并克隆了CD8 T 这些小鼠早期出现的细胞； 2-4 时 CD8 T 细胞耗竭 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. 我们将准备小鼠 T 细胞受体转基因，以研究其成熟， 激活和效应器功能。 2. 我们将鉴定他们的β细胞 使用杂交体设计的特异性抗原，可灵敏检测 编码抗原肽的cDA。 我们将确定 这些细胞归巢到胰岛的机制，发生在 注射后的前三个小时。 4. 我们认为 CD4 T 细胞 仅当 CD8 细胞释放自身抗原后才被激活，我们 相信 B 细胞在发生的多样化中发挥着关键作用 这次活动之后。 这是因为缺乏β的NOD小鼠不 发展为糖尿病。 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 这是赋予这些共刺激活性所必需的 细胞。 最终，我们希望我们的分析能够提供线索 让我们通过注射胰岛素来预防糖尿病，就像我们 有证据表明胰岛素特异性 T 细胞可以阻止过继 我们小鼠的转移和自发性疾病。