Regulation of the Ocular Immune Response by RPE.

RPE 对眼部免疫反应的调节。

• 批准号: 6826386
• 负责人: HUI SHAO
• 金额: $ 25.73万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6826386
• 关键词: MHC class II antigen; T lymphocyte; apoptosis; cell cell interaction; cellular immunity; flow cytometry; gene expression; immune response; immunoregulation; interferon gamma; laboratory mouse; laboratory rat; leukocyte activation /transformation; retinal pigment epithelium; retinoid binding proteins; terminal nick end labeling; tissue /cell culture; uveitis; visual photoreceptor

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）作为实验模型，了解葡萄膜炎（一种 T 细胞介导的眼部自身免疫性疾病）的发病机制。通过对葡萄膜炎大鼠 (EAU) 和视网膜色素上皮 (RPE)（一种可能是葡萄膜 T 细胞靶向的主要实质细胞）进行体外共培养，我们证明正常 RPE 细胞能够抑制葡萄膜 T 细胞功能，包括增殖和细胞因子产生，T 细胞被渲染即可证明这一点。 当它们预先暴露于 RPE 时，它们对 APC 呈递的特定抗原反应低下。另一方面，激活的RPE 能够在对抗致葡萄膜 T 细胞时通过 MHC 分子的表达和细胞因子的产生来促进 T 细胞反应。葡萄膜T细胞和活化的RPE的相互作用引发大量炎症介质，例如TNF-a、IFN-r和NO，这可能会增加靶组织损伤。 该项目的基本假设是，致葡萄膜 T 细胞和 RPE 之间相互作用的结果在该疾病的发病机制中发挥着关键作用。实验旨在确定与非致病性 T 细胞相比，致葡萄膜 T 细胞是否具有更强的能力来逃避 RPE 介导的抑制，或者它们对 RPE 诱导的细胞凋亡具有更强的抵抗力（具体目标 1）。我们还将测试另一种可能性，即致葡萄膜 T 细胞在与 RPE 相互作用时更有能力诱导级联反应。致葡萄膜的 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，进而激活 T 细胞并导致炎症细胞因子和趋化因子的过量产生（具体目标 2）。该实验室在产生自身反应性 T 细胞和 RPE 细胞方面的专业知识以及评估 T 细胞和 RPE 之间相互作用的各种功能测试的可用性将为拟议的研究提供竞争优势。我们的研究结果将为葡萄膜炎的发病机制提供新的见解。