卡培他滨免疫抑制效应的大鼠实验观察

Experimental observations on immunosuppressive effect of capecitabine in rats

目的采用单纯大鼠喂药模型及原位肝移植急性排斥模型,观察卡培他滨(CAP)的免疫抑制效应。方法建立单纯大鼠喂药模型,选取18只成年清洁级雄性BN大鼠,数字随机分为CON组、CAP节拍剂量组(MET组)和CAP足量剂量组(MTD组)。于喂药前、喂药后第7 d、14 d和21d,流式细胞术(FCM)检测外周血T淋巴细胞及其亚群CD4^+和CD8^+T淋巴细胞数目,ELISA检测IL-2和IFN-γ浓度。建立20对Lewis→BN大鼠原位肝移植急性排斥模型,数字随机分为模型.对照组(A组)、他克莫司单药组(B组)他克莫司+节拍剂量CAP组(C组)和他克莫司+足量剂量CAP组(D组)。术后7d处死,流式细胞术(FCM)检测外周血T淋巴细胞及其亚群CD4^+和CD8^+T淋巴细胞数目,ELISA检测IL-2和IFN-γ浓度,HE染色观察移植肝病理变化。结果单纯大鼠喂药模型中,与CON组相比,在14d、21d时,MET组和MTD组中T淋巴细胞、CD4^+和CD8^+T淋巴细胞数目均减少,差异具有统计学意义(P<0.05);IL-2和IFN-γ于给药7 d、14 d和21 d均下降,差异有统计学意义(P<0.05)。移植排斥模型中,与A、B组相比,术后7 d时,C组和D组的大鼠外周血T淋巴细胞、CD4^+和CD8^+T淋巴细胞数目均降低,RAI指数下降,差异具有统计学意义(P<0.05)。结论卡培他滨可降低大鼠外周血T淋巴细胞及其亚群CD4^+和CD8^+T细胞数目,并抑制IL-2和IFN-γ的分泌,具有免疫抑制效应。卡培他滨联用他克莫司可减轻大鼠肝移植术后急性排斥反应强度,预示卡培他滨可能成为一种具有抗肿瘤效应的免疫抑制剂,值得进一步深入探讨。

Ohjective To observe the immunosuppressive effect of capecitabine(CAP)in rat models of drug dosing and acute rejection of orthotopic liver transplantation Methods The rat model of drug dosing was established and 18 adult SPF grade male BN rats were randomly divided into three groups of CON,CAP metronomic dose(MET)and CAP most tolerance dose(MTD).Flow cytometry(FCM)was employed for detecting the counts of T and CD4^+/CD8^+T lymphocytes and enzyme linked immunosorbent assay(ELISA)for detecting the concentrations of interleukin-2(IL-2)and interferon-gamma(IFN-γ)before and at Days 7,14&21 after drug dosing.Twenty pairs of acute rejection models of Lewis→BN rat orthotopic liver transplantation were established.Recipients were randomly divided into four groups of model control(A),FK506 single drug(B),FK506+MET dose CAP(C)and FK506+MTD dose CAP(D).At Day 7 post-operation,flow cytomnetry(FCM)was employed for detecting the counts of T and CD4^+/CD8^+T lymphocytes.Hematoxylin-eosin(HE)staining was utilized for observing the pathological changes of liver transplantation.Results In rat model of drug dosing,as compared with CON group,the counts of T and CD4^+/CD8^+T lymphocytes decreased in MET/MTD group at Days 14&21 with statistically significant differences(P<0.05);IL-2 and IFN-γdecreased after dosing at Days 7,14&21 and the differences were statistically significant(P<0.05).In transplant rejection model,as compared with groups A&B,counts of T and CD4^+/CD8^+T lymphocytes and RAI index decreased in groups C&D and the differences were statistically significant(P<0.05).Conclusions Capecitabine may lower the counts of T and CD4^+/CD8^+T lymphocytes in peripheral blood and suppress the secretions of IL-2 and IFN-γin rat.Capecitabine plus tacrolimus(FK506)reduce the intensity of acute rejection after liver transplantation in rat.It suggests that capecitabine may be an immunosuppressant with anti-tumor effects.Further researches are warranted.