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Regulation of the Ocular Immune Response by Retinal Pigment Epithelium

视网膜色素上皮对眼部免疫反应的调节

基本信息

批准号：
7250146
负责人：
HUI SHAO
金额：
$ 24.98万
依托单位：
UNIVERSITY OF LOUISVILLE
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：
2004-08-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7250146
关键词：
Antigens Apoptosis Apoptotic Autoimmune Diseases Autoimmune Responses Belief Blindness Cell Communication Cell Death Cell physiology Cells Coculture Techniques Condition Disease Epithelial Evolution Experimental Models Eye Goals Hand Immune response In Situ In Vitro Inflammation Inflammatory Interferons Invaded Knowledge Laboratories Lead MHC Class II Genes Mediating Mediator of activation protein Nitric Oxide Outcome Pathogenesis Patients Physiological Play Prevention Production Protein Overexpression Rattus Recruitment Activity Recurrence Regulation Research Research Personnel Resistance Retinal Retinal Pigments Role Series Structure of retinal pigment epithelium T-Cell Activation T-Lymphocyte Testing Tissues Uveitis Virus Diseases autoimmune uveitis autoreactive T cell base chemokine cytokine design insight interstitial retinol-binding protein prevent programs research study response

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this proposed research is to understand the pathogenesis of uveitis, a T cell-mediated autoimmune disease in the eye, using experimental autoimmune uveitis (EAU) as an experimental model. Using in vitro co-culture of uveitigeneic T cells derived from rats with uveitis (EAU) and retinal pigment epithelial (RPE), a major parenchymal cell that might be targeted by uveitogeneic T cells, we have demonstrated that normal RPE cells are capable of inhibiting uveitogeneic T cell functions including proliferation and cytokine production, as evidenced by that T cells are rendered hypo-responsive to their specific antigens presented by APCs when they are pre-exposed to RPE. On the other hand, activated RPE is capable of promoting T cell responses by expression of MHC molecules and production of cytokines upon confronting uveitogenic T cells. The reciprocal interaction of uveitogeneic T cell and activated RPE elicit significant amounts of inflammatory mediators such as TNF-a, IFN-r and NO, which may increase target tissue damage. The underlying hypothesis of this project is that the outcome of interactions between uveitogenic T cells and the RPE play a critic role in the pathogenesis of the disease. Experiments are designed to determine whether uveitogenic T cells have an increased ability, compared to their nonpathogenic counterparts, to escape the suppression mediated by RPE, or they are more resistant to the apoptotic cell death induced by RPE (Specific Aim 1). We will also test an alternative possibility that uveitogenic T cells are more capable of inducing cascading responses upon interacting with RPEs. Uveitogenic T cells may induce increased expression of MHC class II or co-stimulatory molecules on RPE cells, which in turn, activate the T cells and result in excessive production of inflammatory cytokines and chemokines (Specific Aim 2). The expertise of this laboratory in generating both autoreactive T cells and RPE cells and the availability of various functional tests assessing interaction between T cells and RPE will provide a competitive advantage in the proposed studies. The results of our studies will provide new insights into the pathogenesis of uveitis.

描述（由申请人提供）：本研究的长期目标是利用实验性自身免疫性葡萄膜炎（EAU）作为实验模型，了解葡萄膜炎（T细胞介导的眼部自身免疫性疾病）的发病机制。通过体外共培养来自葡萄膜炎（EAU）大鼠和视网膜色素上皮（RPE）（一种可能被葡萄膜生成T细胞靶向的主要实质细胞）的葡萄膜生成T细胞，我们已经证明，正常的RPE细胞能够抑制葡萄膜生成T细胞的功能，包括增殖和细胞因子的产生，正如T细胞在预先暴露于RPE时对APCs呈递的特定抗原反应低下所证明的那样。另一方面，激活RPE