细胞因子和补体遗传多态性对肝移植术后个体化免疫抑制和感染防治的影响及机制研究

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.

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。

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。申请人前期申请者应用DMET芯片、外显子芯片、转录组测序和eQTL建立了肝移植遗传数据库。我们发现包括供受体的CYP3A5、CYP3A4、SUMO4、FMO3、SLC28A3、TLR9、TLR4、SULT1E1、SLC7A8等多个基因在内的单核苷酸多态性与免疫抑制剂他克莫司（TAC）代谢以及术后感染相关。在前期研究的基础上，进一步确定包括供受体CYP3A5，供体CYP3A7、受体CHST1和受体SLC28A3在内的多个基因的单核苷酸多态性对于他克莫司的代谢有着显著的影响。并且通过整合多中心数据，建立了他克莫司的代谢预测模型，为肝移植术后他克莫司个体化用药提供有效依据。同时扩展地研究了肝移植术后新发糖尿病的遗传风险基因并揭示基因间的相互调节网络。此外多组学整合分析首次发现供肝C7 rs6876739、IL-18 rs1946538、SGT1 rs9526974、MBL2 rs11003125和PANX1 rs7947511遗传多态性与肝移植术后早期感染的显著相关，机制研究揭示Panx1通过释放ATP，激活P2X2/Nlrp3/Caspase-1信号通路，释放IL33招募巨噬细胞抵抗MRSA感染。以上研究结果为临床肝移植术后免疫抑制剂他克莫司首次及初期用药剂量提供指南，为降低肝移植术后免疫排斥、感染发生及药物副作用提供理论依据。以上研究结果发表SCI论文9篇，中文核心期刊1篇，培养博士生5名，硕士生5名，授权实用型专利授权5项，授权发明专利1项。同时2018年举办国际学术会议1次，参加2018年全球肝脏移植大会1次。