炎症小体NLRP3在角膜移植免疫排斥反应中的作用及机制研究

角膜移植是角膜盲复明的主要手段，但术后的免疫排斥反应是导致角膜移植失败的最主要原因。本课题组前期研究发现：炎症小体NLRP3通路相关蛋白在因免疫排斥而发生功能衰竭的角膜植片中的表达显著上调；通过小鼠角膜移植模型证实NLRP3、IL-1β以及IL-17等在免疫排斥小鼠的角膜植片中高表达，并且脾脏中Th17细胞的相对含量显著增加；体外实验表明NLRP3-IL1β通路显著促进Th17细胞的分化。以上提示NLRP3-IL-1β-Th17通路在角膜移植免疫排斥反应中起关键作用。基于此，我们拟进一步开展以下研究：①利用NLRP3缺陷小鼠阐明其在角膜移植免疫排斥中作用；②研究NLRP3对抗原递呈细胞功能以及对初始CD4+T细胞增殖分化的影响，阐明其参与免疫排斥反应的分子机制；③阐明干预NLRP3炎症小体信号通路对角膜移植免疫排斥反应的影响。通过此项研究为临床防治角膜移植免疫排斥反应提供理论数据和思路。

Although the corneal transplantation is the main measure for the blindness to recover the sight, the postoperative rejection is the key reason for the corneal allograft rejection. Our previous results indicated that the significantly elevated levels of proteins involved in NLRP3 inflammasome signaling pathway in the dysfunctional corneal allograft caused by immune rejection. We also discovered that the higher levels of NLRP3, IL-1βand IL-17 in the corneal allograft accompanied with immune rejection using corneal transplantation mice models, and elevated relative percentage of Th17 cells in spleens with corneal immune rejection. Moreover, we also found that NLRP3-IL-1βaxis significantly promoted the differentiation of naïve CD4+T cells into Th17 cells through in vitro experiments. The results above suggested the key roles of NLRP3-IL-1β-Th17 axis in mediating the corneal allograft rejection. Based on the above findings, we will further： ① elucidate the roles of NLRP3 in the development of corneal allograft rejection using NLRP3-deficient mouse; ② explore the mechanisms of NLRP3 involved in the development of corneal allograft rejection through studying the influences of NLRP3 on antigen-presenting cells and naïve CD4+T cells; ③ study the effect of corneal allograft rejection by intervening the NLRP3 inflammasome signaling pathway using small molecular compounds. The purpose of this study is to enrich the knowledge of corneal allograft rejection and provide the novel targets for the therapy of allograft rejection.