Molecular Mechanisms Underlying Immune Regulation of Ocular Inflammation

眼部炎症免疫调节的分子机制

• 批准号: 8531938
• 负责人: SHARMILA MASLI
• 金额: $ 42.29万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8531938
• 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' 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

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）：眼部抗原呈现细胞引起的免疫偏差涉及防止炎症的保护性周围免疫反应。这种抗炎免疫反应在避免眼部炎症的潜在盲目作用中起着重要作用。眼APC诱导这种保护反应的独特能力归因于它们在本地微环境中暴露于TGF-2的能力。该提案中描述的研究旨在阐明这种TGF-2暴露于诱导调节性免疫反应时使用的分子机制。第一个特定的目的旨在确定血小板素-1（TSP-1）在诱导调节T细胞外周群中的重要性。由于我们之前证明了TSP-1对于眼部免疫特权至关重要，因此在此目标中实验将使我们能够确定TSP-1对外周免疫效应子的影响。第二个目的旨在研究TSP-1与受体对效应子的相互作用的特定贡献，随后抑制了炎症免疫反应。考虑到具有多种细胞类型特异性生物学作用的大分子（例如TSP-1）的多域结构，这些研究将阐明TSP-1有助于免疫偏差的机制。最终目的旨在解决TSP-1依赖机制在调节自身免疫性眼炎症条件下的相关性，如实验性自身免疫性葡萄膜炎（EAU）和Sjogren综合征相关的眼部表面疾病干眼症所见。由于已知TSP-1在维持免疫特权方面很重要，因此这些研究将使我们能够评估是否应用任何TSP-1依赖机制可以帮助解决慢性眼炎性疾病。这些研究共同可以进一步建立在眼部免疫反应的知识上，并提供对新型治疗策略的见解。

项目成果

Topical Application of TGF-β-Activating Peptide, KRFK, Prevents Inflammatory Manifestations in the TSP-1-Deficient Mouse Model of Chronic Ocular Inflammation.

局部应用 TGF-β 激活肽，KRFK，可预防慢性眼部炎症 TSP-1 缺陷小鼠模型中的炎症表现。

• DOI: 10.3390/ijms20010009
• 发表时间: 2018
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Soriano-Romaní,Laura;Contreras-Ruiz,Laura;López-García,Antonio;Diebold,Yolanda;Masli,Sharmila
• 通讯作者: Masli,Sharmila

Immunomodulatory cross-talk between conjunctival goblet cells and dendritic cells.

• DOI: 10.1371/journal.pone.0120284
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Contreras-Ruiz L;Masli S
• 通讯作者: Masli S

Review of Ocular Immune Privilege in the Year 2010: Modifying the Immune Privilege of the Eye

• DOI: 10.3109/09273948.2010.512696
• 发表时间: 2010-10-01
• 期刊: OCULAR IMMUNOLOGY AND INFLAMMATION
• 影响因子: 3.3
• 作者: Hori, Junko;Vega, Jose L.;Masli, Sharmila
• 通讯作者: Masli, Sharmila

Surgical denervation of ocular sympathetic afferents decreases local transforming growth factor-beta and abolishes immune privilege.

眼部交感神经传入的手术去神经会减少局部转化生长因子-β并消除免疫特权。

• DOI: 10.2353/ajpath.2009.090264
• 发表时间: 2009
• 期刊: The American journal of pathology
• 作者: Vega,JoseL;Keino,Hiroshi;Masli,Sharmila
• 通讯作者: Masli,Sharmila

Conjunctival inflammation in thrombospondin-1 deficient mouse model of Sjögren's syndrome.

• DOI: 10.1371/journal.pone.0075937
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Contreras-Ruiz L;Regenfuss B;Mir FA;Kearns J;Masli S
• 通讯作者: Masli S