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: 6410345
• 负责人: CHARLES A JANEWAY
• 金额: $ 18万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6410345
• 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.

这个项目的总体目标是探索T和B的作用 淋巴细胞在NOD型胰岛素依赖型糖尿病发病及预防中的作用 小鼠 基本上，我们先前的研究表明，NOD中的IDDm 小鼠是由于自身攻击性T细胞之间的平衡发生了变化， 调节其活性或呈现其效应作用的细胞更好地 细胞 该项目将探讨CD 8 T细胞在免疫系统中的作用。 糖尿病进程的开始。 我们分离并克隆了CD 8 T细胞， 在这些小鼠中早期出现的CD 8 T细胞;在2-4 周是众所周知的预防糖尿病。 利用这些克隆的T细胞， 计划实现以下具体目标：1. 我们会准备老鼠 T细胞受体的转基因，为了研究它们的成熟， 激活和效应器功能。 2. 我们会识别出他们的β细胞 特异性抗原，其使用经工程改造的杂交体用于敏感检测 编码抗原肽的cDA。 康贝特人将以 这些细胞归巢到胰岛的机制，这发生在 注射后3小时。 4. 我们认为CD 4 T细胞是 只有在CD 8细胞释放自身抗原后才会被激活， 我相信B细胞在发生的多样化中起着关键作用， 在这次事件之后。 这是因为β缺陷型NOD小鼠不 患上糖尿病 我们将探讨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CD 40配体 这是赋予这些细胞共刺激活性所必需的 细胞 最终，我们希望我们的分析能提供线索， 使我们能够通过注射胰岛素来预防糖尿病， 有证据表明胰岛素特异性T细胞可以阻断过继性T细胞 转移和自发性疾病。