肝移植术后最小化免疫抑制方案可在有效地抗排斥治疗同时明显降低感染率。申请者应用DMET芯片、外显子芯片和eQTL建立了肝移植遗传数据库，发现供受体CYP3A5、受体CYP3A4、供体IL6、IL10、IL18、TLR4与免疫抑制剂他克莫司（TAC）代谢差异相关,供体MBL2、IL18、C7和受体TLR4与术后感染相关。细胞因子（CK）和补体是肝再生、TAC代谢酶CYP3A5、感染标志物MBL2、免疫细胞的重要调节分子。推测肝移植患者体内存在以CYP3A5、MBL2为核心，CK和补体协同作用的调控网络，供受体基因组多遗传位点相互作用可准确预测TAC代谢和感染差异。本项目建立肝移植术后TAC代谢和感染易感性差异多遗传位点预测模型；应用细胞培养、基因转染、动物模型等技术揭示CK和补体在TAC代谢和感染差异产生中的机制；前瞻性研究验证模型。旨在为肝移植术后个体化免疫抑制和感染防治提供新标志物体系。

Strategy of the minimization of the immunosuppression after liver transplantation is not only to effectively treat the patients for the anti-rejection and but also to significantly lower the risk of the infection, a major and severe complication of liver transplantation. We have established the DMET chip, exons chip and eQTL genetic database in liver transplantation. We found that the differential metabolisms of the immunesupressive agent Tacrolimus (TAC) among patients were associated with donor and recipient’s CYP3A5, recipient’s CYP3A4, and donor’s cellular factor (IL6, IL10, IL18, TRL4) respectively. Recipient’s TRL4 and donor’s IL18 and C7 are associated with infection in patients post liver transplant respectively. Cytokines (CK) and complement is the important regulating molecules of liver regeneration, the TAC metabolic enzymes CYP3A5, infection markers MBL, and immune cells. We speculated that a regulatory network including CYP3A5, CK and complements in liver transplant patients, combined with genome genetic loci interaction in donors and recipients can accurately forecast TAC differences in metabolic and infection. Our project is to establish a individualized immunosuppression strategy and an infection control network based on genetic loci as a predictive model after liver transplantation. We will investigate the mechanism by which these identified markers influences the differential TAC metabolism or infection susceptibility by cell culture, gene transfection and animal models, and assess the predictive model by prospective studies. We expect that successful accomplishment of these aims will provide a new marker system for the infection prevention and treatment and optimizing individualized immunosuppression strategy after liver transplantation.