Mechanisms of Ocular Immune Privilege in the Posterior Eye

描述（由申请方提供）：免疫豁免作为一种为器官和组织提供免疫保护的机制，在所有物种中都是保守的。免疫豁免允许在没有炎症的情况下进行免疫保护。当免疫豁免受到损害时，眼睛处于免疫炎症和自身免疫性疾病如葡萄膜炎的风险中。免疫豁免是一个多层次的过程，即使在实验性自身免疫性葡萄膜炎期间，免疫豁免也只是暂时丧失，并恢复以防止疾病的复发（1）。然而，我们的研究表明，一只眼睛的视网膜激光烧伤（RLB）导致激光治疗和未治疗眼睛的眼免疫豁免延长丧失（2）。在这个R21项目中，我们希望利用这些观察结果，并分析导致废除免疫特权的机制。我们提出RLB通过诱导视网膜色素上皮（RPE）及其抑制功能的变化而废除免疫赦免，这反过来导致对实验性自身免疫性葡萄膜炎（EAU）的易感性增加。我们的研究计划将1.）分析RPE抑制功能是如何丧失的以及丧失了什么; 2.）比较在RLB期间或之后可能改变的RPE上的候选调节分子的表达的变化; 3.）确定RLB后小鼠对自身免疫性葡萄膜炎的易感性是否增加。 公共卫生相关性：该R21应用将确定（使用最先进的细胞、分子方法）实验性视网膜激光烧伤如何消除后眼中的免疫豁免。从这些研究中获得的知识将增强我们对眼部免疫稳态的理解，并可能有助于开发新的治疗方法，用于恢复患有创伤或炎症性疾病（如自身免疫性葡萄膜炎）的眼睛的免疫特权状态。

DESCRIPTION (provided by applicant): Immune privilege is conserved in all species as a mechanism to provide immunoprotection for organs and tissues. Immune privilege allows for immune protection in the absence of inflammation. When immune privilege is compromised, the eye is at risk for immune inflammatory and autoimmune diseases such as uveitis. Immune privilege is a multi-layered process and even during experiment autoimmune uveitis, immune privilege is only transiently lost, and returns to prevent a reoccurrence of the disease (1). However, our studies show that retinal laser burn (RLB) in one eye caused an extended loss of ocular immune privilege in both the laser treated and non-treated eye (2). In this R21 project we would like to exploit these observations and analyze the mechanisms that led to the abrogation of immune privilege. We propose that RLB abrogates immune privilege by inducing changes to the retinal- pigmented epithelium (RPE) and its suppressor function which in turn leads to increased susceptibility to experimental autoimmune uveitis (EAU). Our research plan will 1.) Analyze how and what RPE suppression function is lost; 2.) Compare changes in the expression of candidate regulatory molecules on RPE that might change during or after RLB; 3.) Determine if there is increased susceptibility to autoimmune uveitis in mice after RLB. PUBLIC HEALTH RELEVANCE: This R21 application will determine (using state of the art cellular, molecular approaches) how experimental retinal laser burn abrogates immune privilege in the posterior eye. The knowledge gained from these studies will enhance our understanding of ocular immune homeostasis and may aid in the development of new therapies for restoration of the immune privileged status in eyes that suffer from trauma or inflammatory diseases such as autoimmune uveitis.