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

现在有相当多的证据表明，在胰岛素依赖型糖尿病的发展的一个主要因素是自身反应性T细胞的外周调节的主要缺陷。NOD小鼠自发地发展自身免疫性糖尿病，并且已知具有许多固有的免疫调节缺陷，其中之一是T细胞上的细胞毒性T淋巴细胞抗原4（CTLA- 4/CD 152）分子的表达和功能缺陷。CTLA-4是T细胞活化的负调节剂，并且已被描述为负责体内T细胞无反应性起始的分子。我们实验室先前的工作已经表明，通过用抗CTLA-4抗体治疗非自身免疫小鼠引起的CTLA-4功能的抑制导致T细胞对胰岛细胞自身抗原的应答显著增加。另一方面，在易患糖尿病的NOD小鼠中，T细胞对胰岛细胞免疫的应答在开始时很高，而抗体治疗几乎没有效果，这表明CTLA-4在NOD中功能不佳。该提议的第一个目的是确定是否可以通过废除非自身免疫小鼠品系中的CTLA-4功能在体内打破外周耐受。 在这些实验中，我们将试图确定用胰岛细胞作为自身抗原免疫非糖尿病易感小鼠将导致糖尿病发展的条件。在第二个目标下，我们将确定在非自身免疫小鼠中阻断CTLA-4功能是否允许分离胰岛特异性T细胞以及这些T细胞是否具有致病特性。 将来自非自身免疫小鼠的胰岛反应性T细胞克隆与一组NOD衍生的致糖尿病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功能缺陷导致的外周耐受性的破坏如何促成导致IDDM的自身免疫环境。

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.