Molecular mechanisms underlying immune regulation of ocular inflammation

描述(申请人提供)：由眼部抗原提呈细胞诱导的免疫偏离涉及保护性外周免疫反应，以防止炎症。这种抗炎免疫反应在避免潜在的眼部炎症致盲方面发挥了重要作用。眼部APC诱导这种保护性反应的独特能力归因于它们在局部微环境中暴露于转化生长因子-2。这项建议中描述的研究试图阐明这种暴露于转化生长因子-2的APC在诱导调节性免疫反应中所使用的分子机制。第一个具体目的是确定凝血酶反应蛋白-1(TSP-1)在诱导外周调节性T细胞群中的意义。由于我们早些时候证明了TSP-1对眼睛免疫豁免是必不可少的，所以在这个目的上的实验将使我们能够确定TSP-1对外周免疫效应器的影响。第二个目的是研究TSP-1与其受体在效应器上的相互作用，从而抑制炎症免疫反应的具体作用。考虑到像TSP-1这样具有多细胞类型特异性生物学效应的大分子的多结构域结构，这些研究将阐明TSP-1促进免疫偏离的机制。最终目的是探讨TSP-1依赖机制在实验性自身免疫性葡萄膜炎(EAU)和干燥综合征相关眼表疾病干眼中调节自身免疫性眼部炎症状态的相关性。由于已知TSP-1在维持免疫赦免中起重要作用，这些研究将使我们能够评估应用TSP-1依赖的任何机制是否有助于解决慢性眼炎性疾病。总之，这些研究可以进一步建立在眼部免疫反应现有知识的基础上，并为新的治疗策略提供见解。 与公共卫生相关：眼睛的免疫豁免是一种进化现象，它保护眼睛免受潜在的损害视力的炎症免疫反应的影响。了解这种现象背后的免疫学机制有助于改进目前用于治疗眼部炎症的治疗方法。这些研究的长期目标是开发新的抗炎治疗策略来对抗炎症状况，如自身免疫性疾病和移植排斥反应。

DESCRIPTION (provided by applicant): Immune deviation induced by ocular antigen presenting cells involves a protective peripheral immune response that prevents inflammation. Such anti-inflammatory immune response plays a significant role in avoiding potentially blinding effects of ocular inflammation. The unique ability of ocular APCs to induce such a protective response is attributed to their exposure to TGF-2 in their local microenvironment. Studies described in this proposal seek to elucidate molecular mechanisms utilized by such TGF-2-exposed APCs in inducing a regulatory immune response. The first specific aim seeks to determine the significance of thrombospondin-1 (TSP-1) in the induction of a peripheral population of regulatory T cells. Since we demonstrated earlier that TSP-1 is essential for ocular immune privilege, experiments in this aim will allow us to determine the effect of TSP-1 on peripheral immune effectors. The second aim seeks to investigate the specific contribution of the interactions of TSP-1 with its receptors on the effectors, which subsequently suppress inflammatory immune response. Considering the multidomain structure of a large molecule like TSP-1 with multiple cell type specific biological effects, these investigations will clarify mechanisms by which TSP-1 contributes to immune deviation. The final aim addresses the relevance of TSP-1 dependent mechanisms in regulation of autoimmune ocular inflammatory conditions as seen in experimental autoimmune uveitis (EAU) and Sjogren's syndrome associated ocular surface disease dry eye. Since TSP-1 is known to be important in maintaining immune privilege these studies will allow us to evaluate if application of any of the TSP-1 dependent mechanisms can help resolve chronic ocular inflammatory diseases. Together these studies can build further on the existing knowledge of ocular immune responses and provide insights into novel therapeutic strategies. PUBLIC HEALTH RELEVANCE: Immune privilege of the eye is an evolutionary phenomenon that protects the eye from potential vision-compromising inflammatory immune response. Understanding immunologic mechanisms underlying this phenomenon can help improve current therapeutic approaches used to treat ocular inflammation. The long-term goal of these investigations is to develop novel anti-inflammatory therapeutic strategies to counter inflammatory conditions such as autoimmune diseases and transplant rejections.