The Roles of Costimulatory Molecules in EAAU

描述(申请人提供)：实验性自身免疫性前葡萄膜炎 (EAAU)是一种器官特异性自身免疫性疾病，在 近年来作为人类急性前葡萄膜炎的动物模型。在我们的 实验室可通过以下两种方法之一在Lewis大鼠身上诱导该病： 不溶性牛黑色素相关抗原(MAA)单独或与可溶性牛 添加佐剂的MAA。因为这种疾病也可以通过 将CD4T细胞注入幼稚的Lewis大鼠体内，认为EAAU是由 通过T淋巴细胞。然而，自身抗原自身免疫的机制 眼睛内部的发育和分解的机制，很大程度上是 未知。我们的初步研究表明，CD28-B7的阻断 CTLA-4-Fc的相互作用能抑制诱导，并减轻严重程度 EAAU.因此，Lewis大鼠的EAAU模型提供了一个独特的机会 研究共刺激分子在自身免疫性疾病中的作用，包括 位于免疫特权部位(即眼睛)的。 我们建议进行以下研究：1)基因表达的模式和动力学 自然病程中眼内的共刺激分子和细胞因子 EAAU；2)B7介导的共刺激在眼部效应器中的作用 3)CTLA-4-Fc抑制EAAU诱导的作用机制 对MAA有自身免疫力。 我们的研究应该能让我们更好地理解共刺激的作用 对自身抗原作出反应的分子。此外，我们还将深入了解 参与调节共刺激分子的机制，与 设计新的人类急性白血病选择性免疫治疗策略的潜力 前葡萄膜炎。

DESCRIPTION (provided by applicant): Experimental autoimmune anterior uveitis (EAAU), an organ-specific autoimmune disease, has been actively investigated in recent years as an animal model of human acute anterior uveitis. In our laboratory the disease can be induced in Lewis rats by either immunization with insoluble bovine melanin-associated antigen (MAA) alone or with soluble bovine MAA with adjuvant. Since the disease can also be adoptively transferred with primed CD4+ T cells into naive Lewis rats, it is believed that EAAU is mediated by T lymphocytes. However, the mechanism by which autoimmunity to self antigen within the eye develops, and the mechanism by which it resolves, is largely unknown. Our preliminary studies demonstrate that blockade of the CD28-B7 interaction by CTLA-4-Fc can inhibit the induction and reduce the severity of EAAU. Thus, the model of EAAU in the Lewis rat provides a unique opportunity to study the role of costimulatory molecules in autoimmune diseases, including ones in an immunologically privileged site (i.e. the eye). We propose to study the following: 1) The pattern and kinetics of expression of costimulatory molecules and cytokines within the eye during natural course of EAAU; 2) The role of B7-mediated costimulation in the eye during the effector phase of EAAU; 3) The mechanism by which CTLA-4-Fc inhibits the induction of autoimmunity to MAA. Our studies should allow us to better understand the role of costimulatory molecules in response to a self-antigen. Furthermore, we will gain insight into the mechanisms involved in the regulation of costimulatory molecules, with the potential to design new selective immunotherapeutic strategies for human acute anterior uveitis.