Tolerance and autoimmunity in the eye

描述(申请人提供)：自身免疫性葡萄膜炎是一种威胁自身免疫性疾病的视力，每年影响大约20/100,000人。像其他自身免疫性疾病一样，葡萄膜炎似乎是由于T细胞对眼睛内存在的自身抗原的异常激活所致。T细胞是如何被激活的，自身免疫组织破坏的机制还知之甚少。在小鼠中，实验性自身免疫性葡萄膜炎(EAU)可以通过视网膜抗原、光感受器间视黄醇结合蛋白(IRBP)免疫来诱导。本实验室已经优化了人重组IRBP的生产，并将利用这一点来探索介导EAU的IRBP特异性T细胞的性质。T细胞活化的基本过程之一是T细胞与抗原提呈细胞的相互作用，但目前尚不清楚这种相互作用在体内如何影响EAU。在第一个目的中，将研究抗原提呈细胞在IRBP特异性T细胞的启动和效应功能中的作用。这将通过体内调节APC功能和采用转移研究来实现。这些实验将回答有关自身反应性T细胞如何激活，以及眼睛内负责T细胞效应器功能的抗原提呈细胞的性质等重要问题。虽然已经证实了将EAU转移到具有IRBP特异性T细胞的NA小鼠体内，但能够诱发疾病的T细胞的性质尚不清楚。在第二个目标中，一组IRBP特异性T细胞克隆将被鉴定为具有各种功能特性，以及它们将EAU转移到正常小鼠的能力。在第三个目标中，将从精选克隆中分离T细胞受体基因，并用于生产转基因小鼠。这些小鼠为进一步研究EAU的发病机制提供了有价值的新模型系统。为此，我们还将进一步开发在视网膜中表达卵清蛋白的转基因模型系统。这将涉及生产新的转基因小鼠，这些小鼠表达一种形式的卵清蛋白，这种蛋白将保留在视网膜内，而不是被分泌出来。总之，这些研究将提供重要的新信息，并产生一个新的模型系统，从而更好地理解自身免疫性葡萄膜炎的机制。

DESCRIPTION (provided by applicant): Autoimmune uveitis is a sight threatening autoimmune disease affecting some 20/100,000 people per year. Like other autoimmune diseases, uveitis appears to result form the aberrant activation of T cells toward self antigen present within the eye. How the T cells become activated, and the mechanism of autoimmune tissue destruction is poorly understood. In mice, experimental autoimmune uveitis (EAU) can be induced by immunization with the retinal antigen, interphotoreceptor retinol binding protein (IRBP). This laboratory has optimized the production of human recombinant IRBP, and will use this to probe the nature of the IRBP specific T cells which mediate EAU. One of the fundamental processes in T cell activation is the interaction of the T cell with the antigen presenting cell, yet nothing is known about how this interaction affects EAU in vivo. In the first aim, the role of the antigen presenting cell in the priming and effector function of the IRBP specific T cell will be studied. This will be accomplished through in vivo modulation of APC function and adoptive transfer studies. These experiments will answer important questions regarding how the autoreactive T cell becomes activated, and the nature of the antigen presenting cell within the eye itself which is responsible for T cell effector function. While the transfer of EAU into na¿ve mice with IRBP specific T cells has been demonstrated, the nature of the T cell that is capable of inducing disease is not known. In the second aim, a panel of IRBP specific T cell clones will be characterized for a variety of functional properties, as well as their ability to transfer EAU to normal mice. In the third aim, T cell receptor genes from select clones will be isolated and used to produce transgenic mice. These mice will provide a valuable new model system in which to further study the mechanism of EAU. Toward this aim, we will also further develop a transgenic model system in which ovalbumin is expressed in the retina. This will involve the production of new transgenic mice which express a form of ovalbumin which will be retained within the retina, rather than being secreted. Together, these studies will provide important new information as well as produce a new model system resulting in much greater understanding of the mechanisms of autoimmune uveitis.