PD-1/PD-L1对年龄相关性黄斑变性发展的影响及免疫机制的研究

Age-related macular degeneration (AMD) is one of the most common reasons causing blindness over 50s. AMD is a kind of inflamatory disease and T lymphocytes play an important role in the pathogenesis of AMD,while its mechanism remains unknown. Choroidal neovascularization (CNV) is one of the animal models in researching AMD. PD-1/PD-L1 are important costimulatory molecules, which can regulate T lymphocytes, inhibit proliferation of T lymphocytes and secretion of cytokines. We have already established stable laser-induced CNV model, and found that PD-1/PD-L1 have a protective effect on cerebral hemorrhage model. The objective of this study is to evaluate the effect of PD-L1 on AMD progression of mice, to explore the effect of PD-1/PD-L1 on inflammtory microenvironment of CNV mice, and to explore of the relationship between the immune effect of PD-1/PD-L1 and the PI3K/AKT signaling pathway. This study aims to explore the role of PD-1/PD-L1 in immunological mechanism of AMD, providing a new strategy and theoretical foundation for clinical treatment of AMD.

年龄相关性黄斑变性(AMD)是50岁以上人群主要致盲原因之一。AMD是一种炎性疾病，T细胞在AMD发病中起重要作用，但机制不明确。激光诱导脉络膜新生血管(CNV)是研究湿性AMD动物模型之一。PD-1/PD-L1是一对重要的共刺激分子，具有调节T细胞功能、抑制T细胞增殖和细胞因子分泌功能。我们前期研究已成功建立稳定的CNV动物模型，并发现PD-1/PD-L1对于脑出血动物模型有保护作用。本项目将探讨PD-1/PD-L1在AMD免疫机制中作用，包括明确PD-L1对小鼠AMD病情影响；明确PD-L1对CNV小鼠炎性环境影响；明确PD-1/PD-L1发挥炎性作用与PI3K/AKT信号转导通路关系。通过本研究，将明确PD-1/PD-L1在AMD免疫机制中作用，为AMD临床治疗提供新的策略及理论依据。

本课题主要是关于PD-1/PD-L1对年龄相关性黄斑变性发展的影响及免疫机制的研究。在本项研究中，通过建立小鼠CNV模型注射PD-L1蛋白，从细胞、分子等多个层面探讨 PD-1 及其配体PD-L1对CNV小鼠外周及眼内炎症微环境的影响。我们发现CNV小鼠中，IL-2、IL-6、IL-17、IFN-γ等因子升高，Treg 降低，表明PD-1通过抑制T 细胞的增殖、生存及细胞因子的释放，以及促进Treg 细胞的分化发育来对T细胞进行调节。给予PD-L1后，CNV病变得到缓解及延缓，其可能机制为PD-1 与PD-L1结合，抑制T细胞内PI3K/AKT信号转导通路活性。本实验阐明了AMD免疫学机制，包括对炎性细胞、炎症因子的作用及其下游的分子机制。通过体内实验验证发现PD-L1蛋白可以缓解及改善CNV作用，为湿性年龄相关性黄斑变性治疗提供新思路。