New mechanisms by which complementýregulates the pathogenesis of experimental autoimmune uveitis

摘要 自身免疫性葡萄膜炎是一种常见的致盲原因，病因不明，也没有已知的治疗方法。我们 一直在研究各种补体缺乏引起的实验性自身免疫性葡萄膜炎(Eau)。 视网膜抗原主动免疫和过继转移后的成分、抑制物或受体 已经准备好的视网膜抗原特异性T细胞。我们的发现强烈表明补体，特别是补体 补体受体C3aR和C5aR不仅是体内自身反应性T细胞启动所必需的 外周，也包括视网膜中已经被激活的致病T细胞的迁移和/或再刺激。这些 研究结果表明，这些补体受体可能成为治疗EAU的新靶点， 最终，是自身免疫性葡萄膜炎。 在这项拟议的工作中，我们将重点关注补体在调节 使用EAU作为模型，在目标组织中迁移和/或重新刺激已经准备好的自体反应性T细胞。 我们还将使用各种系统和细胞特异性补体相关来阐明潜在的机制 基因敲除小鼠和其他新型试剂。此外，我们将审查这些措施的有效性，并调查 我们的新型补体靶向试剂抑制移行和再转移的潜在机制 刺激视网膜中先前激活的促葡萄膜生成T细胞治疗EAU 老鼠。这些研究将显著提高我们对自身免疫性葡萄膜炎发病机制的理解。 促进针对补体的新疗法的开发，用于治疗这种致盲疾病。

Abstract Autoimmune uveitis, a common cause of blindness, has an unknown etiology and no known cure. We have been studying experimental autoimmune uveitis (EAU) induced in mice deficient in various complement components, inhibitors, or receptors following active immunization with a retinal antigen and the adoptive transfer of already primed retinal antigen-specific T cells. Our findings strongly suggest that complement, particularly the complement receptors C3aR and C5aR, are required for not only the priming of autoreactive T cells in the periphery, but also the migration and/or re-stimulation of already activated pathogenic T cells in the retina. These findings suggest that these complement receptors could be new therapeutic targets for treating EAU and, eventually, autoimmune uveitis. In this proposed work, we will focus on the previously unknown role of complement in regulating the migration and/or re-stimulation of already primed autoreactive T cells in a target tissue, using EAU as a model. We will also elucidate the underlying mechanisms using various systemic and cell-specific complement-related gene knockout mice and other novel reagents. In addition, we will examine the efficacies and investigate the underlying mechanisms of our novel complement-targeted reagents for suppressing the migration and re- stimulation of previously activated uveitogenic T cells in the retina for the treatment of EAU both in mice and in rats. These studies will significantly improve our understanding of the pathogenesis of autoimmune uveitis and facilitate the development of novel complement-targeted therapeutics for the treatment of this blinding disease.