免疫检查点VISTA在自身免疫性葡萄膜炎发病机制中的作用及其作为治疗靶点的研究

自身免疫性葡萄膜炎是一类临床常见的致盲性眼病，发病机制主要是T细胞介导的自身免疫反应。最新研究证实，T细胞激活抑制物免疫球蛋白可变区结构域（VISTA）是目前发现的首个可增强原始T细胞免疫沉默、维持外周T细胞免疫耐受的负性免疫检查点，可抑制多种与自身免疫性葡萄膜炎免疫应答机制十分相似的自身免疫病（如多发性硬化、系统性红斑狼疮等）的发生发展。结合前期研究，我们推测VISTA可能通过抑制多种免疫细胞的活化和功能，在自身免疫性葡萄膜炎中发挥免疫保护作用。本项目拟在实验性自身免疫性葡萄膜炎小鼠、白塞病葡萄膜炎及Vogt-小柳原田病患者中，采用免疫组化染色、流式细胞术等实验技术，确定VISTA在自身免疫性葡萄膜炎中的表达和作用，明确其对淋巴细胞、髓系细胞、视网膜小胶质细胞和色素上皮细胞的调节机制，研究激动性VISTA单克隆抗体的实验治疗作用，为阐明自身免疫性葡萄膜炎的发病机制和靶向治疗提供新思路。

Autoimmune uveitis is a common ocular inflammatory disease which may lead to blindness. T-cell-mediated autoimmunity is believed to be the main pathogenetic mechanism. V-domain Ig suppressor of T cell activation (VISTA) is a novel class of immune checkpoint regulators for naïve T cell quiescence and peripheral T cell tolerance, and was recently found to be able to hamper the progression of several autoimmune diseases such as multiple sclerosis and systemic lupus erythematosus. Based on these recent advances, we propose that VISTA may negatively regulate autoimmune uveitis by inhibiting the activation and function of a variety of immune cells. Our current study aimed to explore the potential role of VISTA in the experimental autoimmune uveitis (EAU) mice model, Behçet’s disease uveitis and Vogt-Koyanagi-Harada disease patients. Multilineages of experimental techniques including immunohistochemical staining, flow cytometry and other immunologic experimental techniques will be used to investigate the expression and immunoregulatory mechanisms of VISTA on lymphocytes, myeloid cells, retinal microglia and retinal pigment epithelial cells. The therapeutic effect of agonistic VISTA monoclonal antibodies will be evaluated in EAU. The aim of this project is to provide new insights into pathogenesis and therapeutic target in autoimmune uveitis.