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）：实验性自身免疫性前葡萄膜炎 （EAAU）是一种器官特异性自身免疫性疾病，已在以下领域得到积极研究： 近年来作为人类急性前葡萄膜炎的动物模型。在我们的 在实验室中，可以通过以下任一方式对 Lewis 大鼠进行免疫诱发疾病： 单独使用不溶性牛黑色素相关抗原 (MAA) 或与可溶性牛黑色素相关抗原 (MAA) 一起使用 MAA 与佐剂。由于这种疾病也可以通过过继传播 将 CD4+ T 细胞启动到幼稚 Lewis 大鼠中，据信 EAAU 是介导的 由T淋巴细胞。然而，针对自身抗原的自身免疫的机制 眼睛内部的发育及其解决机制很大程度上取决于 未知。我们的初步研究表明，CD28-B7 的阻断 CTLA-4-Fc 的相互作用可以抑制诱导并减轻 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）的那些。 我们建议研究以下内容：1）表达模式和动力学 自然过程中眼内的共刺激分子和细胞因子 EAAU； 2）效应器过程中B7介导的共刺激在眼睛中的作用 EAAU 阶段； 3) CTLA-4-Fc抑制诱导的机制 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 参与共刺激分子调节的机制 为人类急性疾病设计新的选择性免疫治疗策略的潜力 前葡萄膜炎。