摘要
目的监测大鼠小体积肝移植术后他克莫司血药浓度以及大鼠生存时间，探究小体积肝移植术后免疫排斥治疗准则。方法用Lewis大鼠和Brown Norway大鼠建立小体积和全肝正常体积移植模型，分为7组：全肝同体移植组（WI）、小体积同体肝移植组（SI）、全肝异体移植组（WA）、小体积异体肝移植组（SA）、全肝异体移植免疫治疗组（WAT）、小体积异体肝移植免疫治疗组（SAT）、小体积异体肝移植免疫治疗调变组（SATa）。术后观察肝组织形态和功能变化，监测免疫排斥情况和他克莫司血药浓度，记录存活状况。结果与WA组比较，SA组汇管区炎症细胞浸润、肝窦内皮细胞炎症改变，T细胞受体（TCR）阳性淋巴细胞比例升高。移植术后4天，外周血检测显示异体移植组CD4＋CD25＋双阳性T淋巴细胞显著低于同体移植组，SA组（0.6%）阳性表达率明显低于WA组（1.8%），差异有统计学意义（P〈0.05）。SAT组他克莫司血药浓度在各时间点显著高于WAT组，SATa组他克莫司血药浓度相对稳定，且SATa组血药浓度和AST显著低于SAT组，差异有统计学意义（P〈0.05）。SATa组肝细胞增殖水平明显高于SAT组，差异有统计学意义（P〈0.05）。生存分析表明WA组累积生存率达85.7%，明显高于SAT组的28.6%，差异有统计学意义（P〈0.05）。SATa组累积生存率达到51.7%。WAT组生存时间为（57.4±25.0）d，SAT组（28.0±29.1）d，SATa组（39.7±29.0） d，明显长于未治疗组，差异有统计学意义（P〈0.05）。细胞增殖与凋亡比率（PRA）随他克莫司用药时间增加而增加，他克莫司血药浓度与AST呈正相关（R＝0.758，P〈0.05），RPA与AST显著相关（R＝－0.962，P〈0.05）。结论他克莫司明显延长了小体积异体肝移植大鼠生存时间。在他克莫司血药浓度和AST血清值方程（TD＝－0.494TC－0.0035AST＋260.487）的指导下调整他克莫司用量，使血药浓度相对稳定，可进一步延长同种异体肝移植大鼠的生存时间。
Objective To detect the plasma concentration of tacrolimus and the survival time of rats after small-volume liver transplantation, and to investigate the criteria for immunological rejection after small-volume liver transplantation.Methods Lewis rats and Brown Norway rats were used to establish a small volume and normal liver volume transplantation model, which were divided into 7 groups： whole liver transplantation group （WI）, small volume allogeneic liver transplantation group （SI）, and whole liver allograft group （WA）, small volume allogeneic liver transplantation group （SA）, whole liver allograft immunotherapy group （WAT）, small volume allogeneic liver transplantation immunotherapy group （SAT）, small volume allogeneic liver transplantation immunotherapy modulation group （SATa）. Morphological and functional changes of liver tissue were studied postoperatively, AST and tacrolimus plasma concentrations were detected, and survival was recorded.Results Compared with the WA group, the inflammatory cells infiltrated in the portal area of the SA group, the inflammatory changes of the sinusoidal endothelial cells, and the proportion of TCRpositive lymphocytes increased. Four days after transplantation, peripheral blood tests showed that CD4＋ CD25＋ double positive lymphocytes were significantly lower in the allograft group than in the allograft group, and the positive expression rate in the SA group （0.6%） was significantly lower than that in the WA group （1.8%）. The differences were statistically significant （P〈0.05）. In the SAT group, the blood concentration of tacrolimus was significantly higher than that in the WAT group at each time point （P〈0.05）. The blood concentration of tacrolimus in the SATa group was relatively stable, and the plasma concentration of the SATa group was stable. And AST was significantly lower than the SAT group, the differences were statistically significant （P〈0.05）. Compared with WAT group, the proliferation and apoptosis rate of hepatocytes in SAT group and SATa group were significantly increased. The proliferation of hepatocytes in SATa group was significantly higher than that in SAT group （P〈0.05）. Survival analysis showed that the cumulative survival rate of the WA group was 85.7%, which was significantly higher than that of the SAT group （28.6%）. The difference was statistically significant （P〈0.05）. The cumulative survival rate of the SATa group was 51.7%. The survival time of WAt group was （57.4±25.0） days, SAT group was （28.0±29.10） days, SATa group was （39.7±29.0） days, which were longer than untreated groups. The ratio of proliferation to apoptosis （PRA） increased with increasing time of tacrolimus. Regardless of blood concentration, tacrolimus plasma concentration was positively correlated with AST （R=0.758, P〈0.05）, indicating RPA was inversely correlated with AST （R=-0.962, P〈0.05）.Conclusion The use of tacrolimus significantly prolonged the survival time of small-volume allogeneic liver transplantation rats. Adjusting the amount of tacrolimus under the guidance of tacrolimus plasma concentration and AST serum value equation TD=-0.494TC-0.0035AST＋ 260.487 to make the blood concentration relatively stable, it can further extend the allogeneic liver transplantation rat time to live.
作者
刘钧
刘小龙
王丹
马延龄
陈亚惊
谷保红
李雪梅
胡继科
张凡
陈昊
Liu Jun;Liu Xiaolong;Wang Dan;Ma Yanling;Chen Yajing;Gu Baohong;Li Xuemei;Hu Jike;Zhang Fan;Chen Hao(Department of Pediatric Surgery,the Central Hospital of Mianyang,Mian Yang 621000,China)
出处
《中华肝胆外科杂志》
CAS
CSCD
北大核心
2018年第11期770-774,共5页
Chinese Journal of Hepatobiliary Surgery
基金
国家自然科学基金（81470791,81376597,81670594）
甘肃省基础研究创新群体项目（1606RJIA328）
中央高校重点项目（lzujbky-2017-79）
甘肃省卫生行业科研计划项目（GSWSKY2017-09）
关键词
小体积肝移植
他克莫司
免疫排斥
Small volume liver transplantation
Tacrolimus
Immune rejection
作者简介
通信作者：陈昊，电子信箱：chenhao3996913@163．com
