TNFAIP8-like 2(TIPE2)蛋白调控角膜移植免疫排斥反应的机制研究

角膜移植术是角膜病盲人复明的主要治疗手段，但术后的免疫排斥反应是导致手术失败的重要原因。我们前期研究发现：①小鼠角膜移植模型中，TIPE2基因缺失会明显促进免疫排斥反应发生，植片存活时间缩短；角膜植片免疫组化、荧光染色及流式分析结果发现，TIPE2缺失小鼠角膜中浸润的免疫细胞数目明显增多，胸腺、脾脏、淋巴结组织中的Treg细胞增殖分化受到明显抑制。②异系移植排斥反应发生时，房水中炎症因子TNF-alpha水平升高，角膜内皮细胞中TIPE2蛋白水平与细胞凋亡呈正相关趋势；体外实验中，TNF-alpha处理角膜内皮细胞可上调TIPE2水平，并促进细胞凋亡，而敲低TIPE2蛋白水平，凋亡增强的现象明显减弱。基于此，本项目拟以TIPE2蛋白为主要研究对象，结合TIPE2基因缺失小鼠，研究TIPE2的适度表达在免疫排斥反应中的关键性作用及调控机制，为临床防治角膜移植免疫排斥反应提供理论数据和思路。

Corneal transplantation is predominant treatment for many disorders of the cornea leading to blindness. Despite advances in microsurgery and immunosuppressive treatment protocols, a significant number of corneal grafts still undergo immune-mediated allograft rejection. Our previous study has found that TIPE2-deficient could promote the corneal allograft rejection. In the TIPE2-deficient corneal allograft, the numbers of infiltrating immune cells were significantly growing and the differentiation of Treg cells were strongly inhibited. In allograft rejection models, TNF-alpha was higher in the cornea and high levels of TIPE2 and apoptosis following TNF-alpha elevation. In vitro, TNF-alpha clearly augments TIPE2 expression and promotes cell apoptosis, knocking down markedly decreased cell apoptosis. The results above suggested the critical roles of TIPE2 in mediating the corneal allograft rejection. Here we will explore the roles of TIPE2 in the development of corneal allograft rejection and investigate the underlying mechanisms. The purpose is to examine the feasibility of TIPE2 as the target of medication treatment, which may provide us new insights into diagnosis and therapy of allograft rejection.