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，其病因不明，也没有已知的治疗方法。我们 一直在研究实验性自身免疫性葡萄膜炎（EAU）诱导的小鼠缺乏各种补体 在用视网膜抗原主动免疫和过继转移后， 视网膜抗原特异性T细胞我们的研究结果强烈表明，补充，特别是 补体受体C3 aR和C5 aR不仅是在免疫系统中引发自身反应性T细胞所必需的， 这不仅可以促进外周的免疫反应，而且还可以促进视网膜中已经活化的致病性T细胞的迁移和/或再刺激。这些 这些发现提示这些补体受体可能是治疗EAU的新的治疗靶点， 最终导致自身免疫性葡萄膜炎 在这项拟议的工作中，我们将重点放在以前未知的作用，补体在调节 已经引发的自身反应性T细胞在靶组织中的迁移和/或再刺激，使用EAU作为模型。 我们还将阐明潜在的机制，使用各种系统性和细胞特异性补体相关的， 基因敲除小鼠和其他新试剂。此外，我们将检验疗效，并调查 我们的新型补体靶向试剂用于抑制迁移和再 刺激视网膜中先前激活的致色素层T细胞以治疗小鼠和小鼠中的EAU 大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认识， 有助于开发用于治疗这种致盲性疾病的新型补体靶向治疗剂。

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.