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: 6301178
• 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: 1999-12-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6301178
• 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 NOD中IDDM发病机理和预防的淋巴细胞 老鼠。 基本上，我们先前的研究表明，IDDM点头 小鼠是由自动攻击T细胞之间平衡的转移导致的 以及调节其活性或呈现其效应子动作下注的细胞 细胞。 该项目将探讨CD8 T细胞在 糖尿病过程的启动。 我们已经孤立和克隆的CD8 T 这些小鼠早期出现的细胞； CD8 T细胞在2-4处的耗竭 已知几周可以预防糖尿病。 使用这些克隆的T细胞，我们 计划追求以下特定目标：1。我们将准备老鼠 T细胞受体的转基因，以研究其成熟 激活和效应子功能。 2。我们将确定他们的beta单元格 使用用于敏感检测的杂种特异性抗原 编码抗原肽的CDA。 我们将确定 这些细胞将这些细胞归为胰岛的机制，发生在 注射后三个小时。 4。我们认为CD4 T细胞是 只有一旦CD8细胞释放自动抗原，才激活，我们 认为B细胞在发生的多元化中起着至关重要的作用 此事件之后。 这是因为缺陷β的点头小鼠没有 患糖尿病。 我们将通过 使用缺乏β细胞或阻塞CD40配体的点头小鼠 这是赋予这些共同刺激活动的必要条件 细胞。 最终，我们希望我们的分析能够提供线索 当我们使用胰岛素注射时，允许我们使用胰岛素预防糖尿病 有证据表明胰岛素特异性的T细胞可以阻止收养 我们的小鼠转移和自发疾病。