The Roles of Costimulatory Molecules in EAAU

描述（由申请人提供）：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，已在 近年来作为人类急性前葡萄膜炎的动物模型。在我们 在实验室中，可以通过以下任一种免疫接种在刘易斯大鼠中诱导该疾病： 不溶性牛黑色素相关抗原（MAA）单独或与可溶性牛黑色素相关抗原（MAA） MAA与佐剂。由于这种疾病也可以通过 致敏的CD4 + T细胞进入幼稚刘易斯大鼠，认为EAAU是介导的 T淋巴细胞。然而，对自身抗原的自身免疫的机制 眼睛内的发展，它解决的机制，在很大程度上是 未知我们的初步研究表明，阻断CD28-B7 与CTLA-4-Fc的相互作用可以抑制诱导并降低 EAAU。因此，刘易斯大鼠的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 在免疫特权部位（即眼睛）。 我们拟研究以下几个方面：（1）表达的模式和动力学的表达， 眼内的共刺激分子和细胞因子 EAAU; 2）B7-介导的共刺激在效应细胞中的作用 3）CTLA-4-Fc抑制EAAU诱导的机制 对MAA的自身免疫。 我们的研究应该让我们更好地了解共刺激的作用， 分子对自身抗原的反应。此外，我们将深入了解 参与共刺激分子调节的机制， 设计新的选择性免疫策略的潜力， 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.