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）：这项拟议的研究的长期目标是使用实验性自身免疫性葡萄膜炎（EAU）作为一种实验模型来理解眼部葡萄膜炎的发病机理，葡萄膜炎是眼中葡萄膜炎的发病机理。 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当APC预先暴露于RPE时，对其特异性抗原的反应性低。另一方面，激活的RPE 能够通过表达MHC分子的表达并在面对葡萄蛋白原T细胞时促进T细胞反应并产生细胞因子。葡萄依二元T细胞和激活的RPE的相互相互作用引起大量炎症介质，例如TNF-A，IFN-R和NO，这可能会增加目标组织损伤。该项目的基本假设是，葡萄膜成生细胞与RPE之间相互作用的结果在疾病的发病机理中起着批评作用。实验旨在确定葡萄膜生成的T细胞是否具有与非致病性对应物相比的能力增加，以逃避由RPE介导的抑制作用，或者它们对由RPE诱导的凋亡细胞死亡具有更大的抵抗力（特定AIM 1）。我们还将测试一种替代可能性，即在与RPE相互作用时，葡萄膜源性T细胞更有能力诱导级联反应。葡萄构成T细胞可能会诱导RPE细胞上MHC II类或共刺激分子的表达增加，而RPE细胞又激活T细胞并导致过度产生炎性细胞因子和趋化因子（特定目标2）。该实验室在产生自动反应性T细胞和RPE细胞的专业知识以及评估T细胞与RPE之间相互作用的各种功能测试的可用性将在拟议的研究中提供竞争优势。我们的研究结果将为葡萄膜炎的发病机理提供新的见解。