肝移植术后排斥严重影响患者生存，目前调控Treg/Th17分化已成为减轻排斥的热点。在前一项国自然项目中发现GSK-3β可调节Treg/Th17平衡和Treg功能，还发现排斥患者外周血中Treg与Th17的中间体IL17+Treg比例明显升高，抗排斥治疗后下降，GSK-3β表达在Treg、IL17+Treg和Th17之间逐渐升高，体外抑制GSK-3β促进IL17+Treg向Treg分化抑制其向Th17分化，并增强其免疫功能。为此我们提出假说：抑制GSK-3β活性促进IL17+Treg向Treg分化及增强其免疫调节功能，减轻肝移植排斥反应。为此我们将建立大鼠肝移植模型，采用流式细胞仪、病毒载体转染等手段，从分子、细胞、动物模型等方面研究，明确GSK-3β通过调控IL17+Treg分化进而影响Treg/Th17平衡及功能最终减轻排斥的分子机制。本项目的成功实施将为提高肝移植长期疗效提供新策略。

Liver transplantation has become a lifesaving procedure for patients with chronic end-stage liver disease, however, rejection is still a major cause of early graft loss and a risk factor for long-term recipient post-transplant survival. Recently, Th17 and regulatory T (Treg) cells are thought to be critically involved in mediating and regulating immunological response of transplantation. Our fingdings in previos National Nature Science Foundation showed that GSK3β inhibition promoted human iTreg differentiation and suppressive function, while inhibiting Th17 differentiation. We also found that the proportion of IL17+Treg, the intermediate between Treg and Th17, in peripheral blood was higher in patients with acute rejection when compared with that of non-acute-rejection patients. Meanwhile, the propotion of IL17+Treg decreased after succesive anti-rejection therapy. The protein level of GSK-3β gradually increased in Treg, IL17+Treg and Th17. Moreover, we also found GSK-3β inhibitor significantly enhanced Treg differentiation and inhibited Th17 cell differentiation from IL17+Treg. We hypothesize that inhibition of GSK-3β alleviates the rejection of liver transplantation via regulating Treg/Th17 cell differentiation from IL17+Treg and enhancing IL17+Treg suppressive function. To verify this hypothesis, flow cytometry, Western Blot, lentiviral vector transduction and RNA interference were applied to investigate the role of GSK-3β in liver transplantation in vivo and vitro. This research could provide new ideas and methods to improve the long-term outcome of liver transplantation.