Role of CD6 in the pathogenesis of autoimmune uveitis

摘要 自身免疫性后葡萄膜炎是一种常见的致盲性疾病，其病因尚不清楚 并且没有治愈方法。视网膜抗原特异性T细胞反应，尤其是Th 17细胞 反应，在发病机制中发挥重要作用。虽然CD 6被确定为一种标志物， 几十年前，它在T细胞调节和疾病发病机制中的确切作用 目前，这种基因工程动物仍然难以捉摸，部分原因是缺乏CD 6基因工程动物。在我们的试点研究中， 在CD 6敲除（KO）小鼠中的实验性自身免疫性葡萄膜炎（EAU）和使用抗CD 6 在野生型小鼠中，我们发现证据表明CD 6是一种 自身免疫性葡萄膜炎发病机制中的关键T细胞调节因子及其靶向CD 6 使用单克隆抗体可能有效治疗这种疾病。此外，我们发现了一种新的CD 6 可能比其目前已知的配体（CD 166）对CD 6功能更重要的配体 并表明这种新的CD 6配体的缺乏导致EAU减弱。在这个项目中， 使用我们自己开发和合作伙伴提供的独特试剂，包括CD 6 KO小鼠、两种CD 6配体之一的KO小鼠、CD 6人源化小鼠、EAU自身抗原- 特异性TCR转基因小鼠、特异性T细胞识别四聚体和小鼠抗小鼠CD 6 与人CD 6交叉反应的功能中和单克隆抗体，我们将研究机制， 通过分析CD 6在调节自身反应性T细胞中的作用， 细胞活化、增殖、存活和浸润。我们亦会研究 靶向CD 6的mAb改善EAU和潜在机制。这些研究将阐明 关于CD 6在调节先前体外产生的T细胞中的作用的争议 这些研究有助于理解CD 6调节自身反应性T细胞的机制， 反应在自身免疫性葡萄膜炎的发病机制，奠定了坚实的基础， 开发CD 6靶向mAb作为治疗这种致盲性疾病的新疗法。

Abstract Autoimmune posterior uveitis, a common cause of blindness, has an unknown etiology and no cure is available. Retinal antigen-specific T cell responses, especially Th17 cell responses, play an important role in the pathogenesis. Although CD6 was identified as a marker of T cells decades ago, its precise role in T cell regulation and the pathogenesis of diseases remains elusive, partly due to the lack of CD6 gene-engineered animals. In our pilot studies on experimental autoimmune uveitis (EAU) in CD6 knockout (KO) mice and using anti-CD6 monoclonal antibodies (mAbs) in wild type mice, we found evidence suggesting that CD6 is a critical T cell regulator in the pathogenesis of autoimmune uveitis and that targeting of CD6 using mAbs could be effective in treating this disease. In addition, we identified a novel CD6 ligand that could be more important for CD6 function than its currently known ligand (CD166) and showed that deficiency of this new CD6 ligand leads to attenuated EAU. In this project, using unique reagents developed by ourselves and provided by our collaborators, including CD6 KO mice, KO mice for either of the two CD6 ligands, CD6 humanized mice, EAU autoantigen- specific TCR transgenic mice, specific T cell-recognizing tetramers, and mouse anti-mouse CD6 function neutralizing mAbs that cross-react with human CD6, we will study mechanisms by which CD6 regulates the development of EAU by dissecting its role in regulating autoreactive T cell activation, proliferation, survival, and infiltration. We will also study the extent to which the CD6-targeted mAbs ameliorate EAU and the underlying mechanisms. These studies will clarify the controversy about the role of CD6 in regulating T cells generated by previous in vitro studies, help in understanding the mechanism by which CD6 regulates autoreactive T cell responses in the pathogenesis of autoimmune uveitis, and lay a solid foundation for the development of CD6-targeted mAbs as a new therapy for treating this blinding disease.