Molecular Mechanisms Underlying Immune Regulation of Ocular Inflammation

描述（由申请方提供）：眼部抗原呈递细胞诱导的免疫偏离涉及预防炎症的保护性外周免疫应答。这种抗炎免疫应答在避免眼部炎症的潜在致盲作用中起重要作用。眼部APC诱导这种保护性应答的独特能力归因于它们在其局部微环境中暴露于TGF-2。本提案中描述的研究试图阐明这种TGF-2暴露的APC在诱导调节性免疫应答中所利用的分子机制。第一个具体目标是确定血小板反应蛋白-1（TSP-1）在诱导外周调节性T细胞群中的意义。由于我们先前证明了TSP-1对于眼部免疫豁免是必不可少的，因此在此目的中的实验将使我们能够确定TSP-1对外周免疫效应物的影响。第二个目的是研究TSP-1与其受体对效应器的相互作用的具体贡献，其随后抑制炎症免疫反应。考虑到大分子如TSP-1的多结构域结构具有多种细胞类型特异性生物学效应，这些研究将阐明TSP-1导致免疫偏离的机制。最终目的是解决TSP-1依赖性机制在调节自身免疫性眼部炎性病症中的相关性，如在实验性自身免疫性葡萄膜炎（EAU）和干燥综合征相关的眼表疾病干眼症中所见。由于已知TSP-1在维持免疫豁免中是重要的，这些研究将使我们能够评估是否应用任何TSP-1依赖性机制可以帮助解决慢性眼部炎症性疾病。这些研究可以进一步建立在现有的眼部免疫反应的知识，并提供新的治疗策略的见解。

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.