The Roles of Costimulatory Molecules in EAAU

共刺激分子在 EAAU 中的作用

• 批准号: 6781054
• 负责人: HUI SHAO
• 金额: $ 17.88万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6781054
• 关键词: CD28 molecule; RNase protection assay; antigen presenting cell; autoantigens; autoimmune disorder; chemokine; complement inhibitors; complement pathway; cytokine; enzyme linked immunosorbent assay; flow cytometry; gene expression; immunocytochemistry; immunopathology; iridocyclitis; laboratory rat; monoclonal antibody; pathologic process; polymerase chain reaction; single cell analysis

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.

描述（由申请人提供）：实验性自身免疫前葡萄膜炎 （EAAU）是一种特定器官特异性的自身免疫性疾病，已被积极研究 近年来是人类急性前葡萄膜炎的动物模型。在我们的 实验室该疾病可以通过免疫来诱导刘易斯大鼠 单独或与可溶性牛单独或与不溶性牛黑色素相关抗原（MAA） MAA佐剂。由于该疾病也可以通过 启动的CD4+ T细胞成幼稚的刘易斯大鼠，据信EAAU是介导的 通过T淋巴细胞。但是，自身免疫自身抗原的机制 眼睛内部发展，其解决的机制在很大程度上是 未知。我们的初步研究表明，CD28-B7的封锁 CTLA-4-FC相互作用可以抑制诱导并降低 eaau。因此，刘易斯大鼠中的EAAU模型为 研究共刺激分子在自身免疫性疾病中的作用，包括 在免疫学特权部位（即眼睛）中的一个。 我们建议研究以下内容：1）表达的模式和动力学 在自然过程中，眼睛内的共刺激分子和细胞因子 eaau; 2）在效应器期间，B7介导的共刺激在眼中的作用 EAAU阶段； 3）CTLA-4-FC抑制诱导的机制 自动免疫到MAA。 我们的研究应该使我们能够更好地理解共同刺激的作用 分子响应自我抗原。此外，我们将深入了解 调节共刺激分子的机制，与 为人类急性设计新的选择性免疫治疗策略的潜力 前葡萄膜炎。