Regulation of the Ocular Immune Response by RPE.

描述(申请人提供)：这项拟议研究的长期目标是以实验性自身免疫性葡萄膜炎(EAU)为实验模型，了解葡萄膜炎的发病机制，这是一种T细胞介导的眼睛自身免疫性疾病。通过体外共培养葡萄膜炎(EAU)大鼠的葡萄膜生成T细胞和视网膜色素上皮(RPE)，我们证明了正常的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，这表明当APC预先暴露于RPE时，T细胞对其提供的特定抗原的反应减弱。另一方面，激活的RPE 在面对葡萄膜源性T细胞时，能够通过表达MHC分子和产生细胞因子来促进T细胞反应。葡萄膜生成的T细胞与活化的RPE相互作用，可产生大量的炎性介质，如肿瘤坏死因子-α、干扰素-r和一氧化氮，从而增加靶组织损伤。 这个项目的基本假设是葡萄膜生成T细胞和RPE之间相互作用的结果在疾病的发病机制中起着关键作用。实验旨在确定与非致病T细胞相比，葡萄膜生成T细胞是否有更强的能力逃避RPE介导的抑制，或者它们对RPE诱导的细胞凋亡更具抵抗力(特定目标1)。我们还将测试另一种可能性，即葡萄膜源性T细胞在与RPE相互作用时更有能力诱导级联反应。葡萄胎T细胞可诱导RPE细胞表面MHC-II类或共刺激分子的表达增加，进而激活T细胞，导致炎性细胞因子和趋化因子的过度产生(特异性目标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制提供新的见解。

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.