To produce transgenic mice which express T cell receptors specific for (IRBP).

描述(申请人提供)：自身免疫性后葡萄膜炎是一种T细胞介导的自身免疫性疾病，其特征是单核细胞渗入视网膜和不可逆光感受器破坏。虽然原因不明，但可以通过光感受器间视黄酸结合蛋白(IRBP)免疫小鼠诱导实验性自身免疫性葡萄膜炎(EAU)。EAU领域以及其他自身免疫性疾病模型的大量研究表明，自身免疫性疾病的主要原因是免疫耐受机制的失败。T细胞受体(TCR)转基因小鼠已经并将继续提供关于耐受诱导机制和自身免疫组织破坏机制的大量重要信息，特别是在多发性硬化症和糖尿病领域。在这项探索性/发展性研究拨款申请中，申请人提议开发具有IRBP特异性的TCR转基因小鼠，作为EAU的新模型。申请人已成功地从三个IRBP特异性T细胞克隆中克隆了编码TCRα和β链的全长cDNA，并正在从另外两个T细胞克隆中克隆受体基因。在第一个目标中，申请者将从两个不同的T细胞克隆中产生两个转基因小鼠系。在第二个目标中，申请人将对这些线进行初步表征，以便将它们确立为对eau有用的模型。这些小鼠将被提供给葡萄膜炎研究社区，并为葡萄膜炎研究创造有价值的新模型。使用这些小鼠进行的研究可能会带来治疗葡萄膜炎的新疗法。 公共卫生意义：该项目将为自身免疫性葡萄膜炎产生新的转基因小鼠模型，这是一种严重威胁自身免疫性疾病的视力。针对多发性硬化症和糖尿病的类似的小鼠模型已经被制造出来，并在这些领域取得了巨大的进步。这些小鼠将被提供给研究界，从而促进治疗自身免疫性葡萄膜炎的新研究。

DESCRIPTION (provided by applicant): Autoimmune posterior uveitis is a T cell mediated autoimmune disease characterized by mononuclear infiltrate into the retina and irreversible photoreceptor destruction. While the cause is unknown, experimental autoimmune uveitis (EAU) can be induced in mice through immunization with interphotoreceptor retinoid binding protein (IRBP). Numerous studies in the EAU field as well as other autoimmune disease models suggest that the primary cause of autoimmune disease is a failure of immune tolerance mechanisms. T cell receptor (TCR) transgenic mice have provided, and continue to provide, a wealth of important information on mechanisms of tolerance induction as well as mechanisms of autoimmune tissue destruction, particularly in the multiple sclerosis and diabetes fields. In this exploratory/developmental research grant application, the applicant proposes to develop TCR transgenic mice with specificity for IRBP as a new model for EAU. The applicant has successfully cloned full length cDNAs encoding the alpha and beta chains of the TCR from three IRBP specific T cell clones, and is in the process of cloning the receptor genes from two other T cell clones. In the first aim, the applicant will generate two lines of transgenic mice from two different T cell clones. In the second aim, the applicant will perform the initial characterization of the lines in order to establish them as useful models for EAU. These mice will be made available to the uveitis research community and create valuable new models for uveitis research. Studies using these mice may lead to new therapies for the treatment of uveitis. PUBLIC HEALTH RELEVANCE: This project will generate new transgenic mouse models for autoimmune uveitis, a severe sight threatening autoimmune disease. Similar mouse models have been produced for multiple sclerosis and diabetes and have been responsible for dramatic advances in those fields. These mice will be made available to the research community and thus foster new research into cures or treatment for autoimmune uveitis.