儿童肝移植术后撤除免疫抑制剂对患儿免疫耐受影响的研究

Effects of withdrawal of immunosuppressive agents on immune tolerance after liver transplantation in children

目的研究儿童肝移植术后停用免疫抑制的可行性,探究影响患儿免疫耐受的相关因素。方法收集2013年1月至2017年1月在天津市第一中心医院儿童器官移植科接受肝移植手术且术后进行免疫抑制剂撤除的14例患儿资料。其中,男8例,女6例;体质量指数(body mass index,BMI)为(20.32±4.65)kg/m^(2);受者移植时患儿年龄范围为0.58~0.71岁,中位年龄为0.58岁;纳入研究时患儿年龄范围为2.65~4.52岁,中位年龄为3.75岁;移植术后至纳入研究时间间隔为(3.08±1.10)年。供者中,男6例,女8例,供者年龄为(22.84±13.93)岁。14例患儿的移植病因均为胆道闭锁,10例为活体肝移植,4例为尸体肝移植。参与撤除免疫抑制剂临床研究的患儿中,4例为移植后淋巴增殖性疾病(post transplant lymphoproliferative disorder,PTLD)而撤除免疫抑制剂。所有患儿移植术后进行免疫治疗,>6岁的患儿采用激素+他克莫司(tacrolimus,FK506)+吗替麦考酚酯三联用药方案,≤6岁的患儿采用激素+FK506二联用药方案。14例患儿中,10例按撤除方案撤除免疫抑制剂,4例PTLD患儿根据病理类型和临床症状单独进行免疫抑制减停治疗。所有患儿定期检测肝功能,并于纳入研究时、纳入研究1年和2年时进行程序性肝活检,采用苏木精-伊红(hematoxylin and eosin,HE)染色并通过Banff标准和Ishak评分系统评估患儿肝脏急性排斥反应和纤维化程度。结果14例患儿中5例成功停用免疫抑制剂,实现免疫耐受;9例患儿免疫不耐受,其中3例在随访过程中肝功能正常,程序性活检时肝脏病理结果考虑为排斥反应;其余6例在随访过程中出现肝功能异常,此6例患儿恢复免疫抑制治疗后,肝功能均恢复到正常水平。与免疫不耐受的患儿相比,免疫耐受的患儿在移植时年龄较小,移植时的中位年龄为0.58岁,范围为0.50~0.58岁,免疫不耐受的患儿移植时的中位年龄为0.67岁,范围为0.58~2.04岁,差异具有统计学意义(P=0.012,Z=-2.51);免疫耐受的患儿直接胆红素(direct bilirubin,DBIL)水平较免疫不耐受患儿低,免疫耐受患儿移植时的DBIL中位值为2.47μmol/L,范围为2.23~2.53μmol/L,免疫不耐受患儿移植时的DBIL中位值为2.63μmol/L,范围为2.52~2.99μmol/L,差异具有统计学意义(P=0.004,Z=-2.87)。结论儿童肝移植术后出现免疫耐受的比例较高,患儿年龄、DBIL水平影响患儿免疫耐受。

Objective To explore the feasibility of withdrawing immunosuppression after pediatric liver transplantation(LT)and to explore the related influencing factors of immune tolerance.Methods Clinical data were retrospectively reviewed for 14 children undergoing LT and withdrawing immunosuppressant postoperatively from January 2013 to January 2017.There were 8 boys and 6 girls with a body mass index(BMI)of(20.32±4.65)kg/m^(2).The age of recipients at the time of transplantation ranged from 0.58 to 0.71 years and the median age was 0.58 years.The recruiting age ranged from 2.65 to 4.52 years and the median age was 3.75 years.And the interval from transplantation to inclusion was(3.08±1.10)years.Among donors,there were 6 males and 8 females with an age range of(22.84±13.93)years.In 14 cases,liver transplant was performed for patients with biliary atresia,including living donor liver transplantation(n=10)and cadaveric liver transplantation(n=4).Among participants in immunosuppressant withdrawing,4 cases had immunosuppressant removed for post transplant lymphoproliferative disorder(PTLD).All of them received immunotherapy post-LT.Children aged>6 years received a triple regimen of steroid+tacrolimus(FK506)+montecoculphate while those aged≤6 years had a double regimen of hormone+FK506.In 10 cases,immunosuppressant was withdrawn according to the withdrawal plan.Four PTLD children received immunosuppressive tapering alone according to pathological type and clinical symptoms.Periodic liver function tests and programmed liver biopsies were performed at the beginning of the study,1 year and 2 years.Hematoxylin eosin(HE)staining was performed for evaluating acute liver rejection and fibrosis by Banff standard and Ishak scoring system.Results Among them,5/14 children successfully stopped immunosuppressive to achieve immune tolerance.Nine children became immune intolerant and 3 had normal liver function during follow-ups.However,the pathological results of programmed liver biopsy hinted at rejection.The remaining 6 cases showed abnormal liver function during follow-ups and liver function normalized after resuming immunosuppressive therapy.As compared with immune intolerants,age at the time of transplantation was smaller for immune tolerants.The median age of transplantation was 0.58(0.50~0.58)years.The age of immune intolerants during transplantation was 0.67(0.58~2.04)years and the difference was statistically significant(P=0.012,Z=-2.51).The level of direct bilirubin(DBIL)in immune tolerants was lower than that in immune intolerants.The median value of DBIL was 2.47(2.23~2.53)μmol/L in immune tolerants and 2.63(2.52~2.99)μmol/L in immune intolerants and the difference was statistically significant(P=0.004,Z=-2.87).Conclusions The proportion of immune tolerance after pediatric liver transplantation remains high and age and DBIL level affect immune tolerance.