REG. OF T CELL AUTOREACTIVITY IN IDDM BY CTLA-4/CD152

注册。

• 批准号: 6381951
• 负责人: Jon D Piganelli
• 金额: $ 7.19万
• 依托单位: CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6381951
• 关键词: CD antigens; CD28 molecule; NOD mouse; T lymphocyte; age difference; antigen antibody reaction; autoantigens; cellular immunity; cyclophosphamide; cytogenetics; genetically modified animals; immune tolerance /unresponsiveness; immunocytochemistry; immunoregulation; injection /infusion; insulin dependent diabetes mellitus; laboratory mouse; leukocyte activation /transformation; pancreatic islets; pathologic process; tissue /cell culture; urinalysis

There is now a considerable body of evidence suggesting that a major factor in the development of IDDM is a primary defect in the peripheral regulation of self-reactive T cells. The NOD mouse develops autoimmune diabetes spontaneously and is known to have a number of inherent immunoregulatory defects, one of which is deficient expression and function of the molecule, cytotoxic T lymphocyte antigen 4 (CTLA- 4/CD152) on T cells. CTLA-4 is a negative regulator of T cell activation and has been described as the molecule responsible for the initiation of T cell anergy in vivo. Previous work by our lab has shown that inhibition of CTLA-4 function, caused by treating non-autoimmune mice with anti- CTLA-4 antibody, leads to a dramatic increase in the T cell response to islet cell autoantigen. On the other hand, in diabetes-prone NOD mice, T cell responses to islet cell immunization are high to begin with and antibody treatment has little effect, one indication that CTLA-4 is not functioning well in the NOD. The first aim in this proposal is to determine whether peripheral tolerance can be broken in vivo via abrogation of CTLA-4 function in non-autoimmune mouse strains. In these experiments, we will attempt to define conditions under which immunization of non-diabetes-prone mice with islet cells as self-antigen will lead to development of diabetes. Under the second aim, we will determine whether blocking CTLA-4 function in non-autoimmune mice will allow for the, isolation of islet-specific T cells and whether those T cells have pathogenic properties. Islet-reactive T cell clones from nonautoimmune mice will be compared to a panel of NOD-derived diabetogenic T cell clones. These studies will allow us to determine how a breakdown in peripheral tolerance due to defective function of CTLA-4 contributes to the autoimmune environment that results in IDDM.

现在有大量证据表明，IDDM发展的主要因素是自反应性T细胞外周调控中的主要缺陷。 NOD小鼠会自发地发育自身免疫性糖尿病，并已知有许多固有的免疫调节缺陷，其中一种是分子的缺乏表达和功能，细胞毒性T淋巴细胞抗原4（CTLA-4/CD152）在T细胞上。 CTLA-4是T细胞活化的负调节剂，已被描述为负责T细胞在体内启动的分子。我们的实验室的先前工作表明，通过使用抗CTLA-4抗体处理非自动免疫小鼠引起的CTLA-4功能的抑制作用导致T细胞对胰岛细胞自动抗原的T细胞反应显着增加。另一方面，在容易发生糖尿病的小鼠中，T细胞对胰岛细胞免疫的反应很高，并且抗体治疗的作用很小，一种表明CTLA-4在点头中的功能不佳。该提案的第一个目的是确定是否可以通过废除非自动免疫小鼠菌株中的CTLA-4功能在体内破坏外围耐受性。 在这些实验中，我们将尝试定义条件，在该条件下，由于自我抗原将导致糖尿病的发育，因此用胰岛细胞对非糖尿病的免疫接种。在第二个目标下，我们将确定在非自动免疫小鼠中阻断CTLA-4功能是否将允许分离胰岛特异性T细胞，以及这些T细胞是否具有致病性。 来自非自动免疫小鼠的胰岛反应性T细胞克隆将与NOD衍生的糖尿病性T细胞克隆进行比较。这些研究将使我们能够确定由于CTLA-4功能缺陷而导致的外周公差的细分如何有助于导致IDDM的自身免疫环境。