Molecular mechanisms underlying immune regulation of ocular inflammation

眼部炎症免疫调节的分子机制

基本信息

批准号：
8320295
负责人：
SHARMILA MASLI
金额：
$ 5.4万
依托单位：
SCHEPENS EYE RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8320295
关键词：
Address Anti-Inflammatory Agents Anti-inflammatory Antigen-Presenting Cells Antigens Autoimmune Diseases Autoimmune Process Biological Candidate Disease Gene Cell Communication Chronic Delayed Hypersensitivity Development Disease Environment Exposure to Eye Genes Goals Graft Rejection Immune Immune Tolerance Immune response Immunologics Inflammation Inflammatory Inflammatory Response Investigation Knowledge Mediating Microarray Analysis Molecular Molecular Analysis Mus Ocular Pathology Peptides Peripheral Play Population Prevention Proteins Regulation Regulatory T-Lymphocyte Role Sjogren&apos s Syndrome Spleen Structure T-Lymphocyte THBS1 gene TNF gene TNFRSF1B gene Testing Therapeutic Therapeutic Intervention Thrombospondin 1 Transplantation Vision Visual anterior chamber autoimmune uveitis base cell type eye dryness improved insight mRNA Differential Displays novel novel therapeutics ocular surface peripheral tolerance prevent receptor research study response

项目摘要

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.

描述（由申请人提供）：由眼部抗原呈递细胞诱导的免疫偏差涉及预防炎症的保护性外周免疫反应。这种抗炎免疫反应在避免眼部炎症潜在致盲效应方面发挥着重要作用。眼 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 TGF-2。该提案中描述的研究旨在阐明此类暴露于 TGF-2 的 APC 在诱导调节性免疫反应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 细胞群中的重要性。由于我们之前证明了 TSP-1 对于眼部免疫特权至关重要，因此该目的的实验将使我们能够确定 TSP-1 对外周免疫效应器的影响。第二个目标旨在研究 TSP-1 与其受体相互作用对效应器的具体贡献，从而抑制炎症免疫反应。考虑到像 TSP-1 这样的大分子的多结构域结构具有多种细胞类型特异性生物效应，这些研究将阐明 TSP-1 导致免疫偏差的机制。最终目标是解决 TSP-1 依赖性机制在调节自身免疫性眼部炎症状况中的相关性，如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。由于已知 TSP-1 对于维持免疫特权很重要，这些研究将使我们能够评估应用任何 TSP-1 依赖性机制是否可以帮助解决慢性眼部炎症疾病。这些研究共同可以进一步建立眼部免疫反应的现有知识，并为新的治疗策略提供见解。