芳香烃受体的激活在大鼠肝移植免疫应答中的作用及机制研究  

Role and mechanism of Aryl hydrocarbon receptor in immune response in rat with liver transplantation

作　　者：曹婉悦 陆晶 徐军明 Cao Wanyue;Lu Jing;Xu Junming(Department of General Surgery,Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 201600,China)

机构地区：[1]上海交通大学医学院上海市第一人民医院普外科,201600

出　　处：《中华普通外科学文献（电子版）》2022年第3期177-182,共6页Chinese Archives of General Surgery(Electronic Edition)

基　　金：国家自然科学基金资助项目(81600595,81970568)。

摘　　要：目的芳香烃受体(AhR)是一种配体激活性转录因子,可以影响T细胞分化,在多种免疫性疾病中发挥作用,本研究主要探索AhR在大鼠肝移植免疫应答中的作用以及机制。方法建立大鼠肝移植同基因耐受模型和异基因排斥模型,术后1、3、7、14 d检测各组AhR和程序性死亡(PD-1)表达量。对肝移植排斥模型进行不同处理并分组。A组:对照组,腹腔注射(i.p.)羧甲基纤维素钠(CMC-Na)1 ml;B组:200 mg·kg^(-1)·d^(-1)的3,4-DAA(i.p.);C组:10 mg·kg^(-1)·d^(-1)的CH223191(i.p.);D组:200 mg·kg^(-1)·d^(-1)的3,4-DAA和10 mg·kg^(-1)·d^(-1)的CH223191(i.p.)。7 d后采集受体外周血检测肝功能指标及CD4^(+)Foxp3^(+)T细胞和CD4^(+)PD-1^(+)T细胞占比,收集大鼠移植肝组织进行病理学检查,采用Banff分级评估排斥活动指数(RAI),并通过免疫印迹法、qPCR检测移植肝组织AhR、PD-1的变化。结果在肝移植排斥模型中AhR和PD-1表达量随着时间逐渐降低,在肝移植耐受模型中逐渐增加。与A组相比,B组受体大鼠RAI降低,存活时间延长,移植排斥减轻;而C组肝功能指标明显上调,RAI升高,移植排斥反应加重;D组与A组差异不明显。AhR和PD-1表达以及CD4^(+)Foxp3^(+)T细胞、CD4^(+)PD-1^(+)T细胞占比在受体中呈现相同的趋势。结论随着肝移植排斥反应的加重,AhR和PD-1表达降低,反之亦然。AhR激活可通过增加调节性T细胞的比例和PD-1的表达,有效降低大鼠肝移植排斥反应的发生。AhR有可能成为临床肝移植术后排斥治疗的新靶点。Objective Aryl hydrocarbon receptor(AhR)is a ligand-activated transcription factor,which can affect T cell differentiation and plays a role in various immune diseases.This study mainly explores the role and mechanism of AhR in the immune response after liver transplantation(LT)in rats.Methods The LT rat models of syngeneic tolerance and allogeneic rejection were established,and the expression levels of AhR and PD-1 in each group were detected at 1,3,7 and 14 days after LT.Then the LT rejection models were divided into four groups with different treatments(i.p.).Group A,1 ml CMC-Na;Group B,200 mg·kg^(-1)·d^(-1)3,4-DAA;Group C,10 mg·kg^(-1)·d^(-1) CH223191;Group D,200 mg·kg^(-1)·d^(-1)3,4-DAA and 10 mg·kg^(-1)·d^(-1) CH223191.After 7 days,the peripheral blood of the recipients was collected to detect liver function and the percentage of CD4^(+)Foxp3^(+)T cells and CD4^(+)PD-1^(+)T cells.The liver of recipient rats was collected for pathological examination,and the rejection activity index(RAI)was evaluated by Banff.The changes of AhR and PD-1 in liver tissues were detected by Western blotting and qPCR.Results The expression levels of AhR and PD-1 decreased gradually in the LT rejection model,while increased gradually in LT tolerance model.Compared with group A,RAI was decreased,survival time was prolonged and graft rejection was alleviated in group B.In group C,liver function index was significantly up-regulated,RAI was increased,and LT rejection was aggravated.There was no significant difference between group D and group A.The expression of AhR,PD-1,the percentage of CD4^(+)Foxp3^(+)T cells and CD4^(+)PD-1^(+)T cells were the same trend in recipient liver.Conclusions The expression of AhR and PD-1 decreased with the aggravation of LT rejection,and vice versa.Moreover,AhR activation can effectively reduce the occurrence of acute rejection in rats by increasing the proportion of Treg and the expression of PD-1,which suggests that AhR may be a new target for rejection therapy after LT.

关 键 词：大鼠 肝移植 芳香烃受体 移植排斥反应 程序性死亡 调节性T细胞 

分 类 号：R392.4[医药卫生—免疫学]