Notch信号通路抑制剂在小鼠异基因骨髓移植后急性移植物抗宿主病中的作用  

Notch signal pathway inhibitor alleviates acute graft-versus-host-disease after allogeneic bone marrow transplantation in murine model

作　　者：郭冬梅[1] 李纯璞[1] 毕高峰[1] 刘双[1] 杜书静[1] 刘玉玉[1] 刘芹芹[1] 滕清良[1] 

机构地区：[1]泰安市中心医院,山东泰安271000

出　　处：《中华器官移植杂志》2016年第4期236-241,共6页Chinese Journal of Organ Transplantation

摘　　要：目的探讨Notch信号通路抑制药物r分泌酶抑制剂（γ-secretase inhibtor，GSI）对小鼠异基因骨髓移植（allo-BMT）后急性移植物抗宿主病（aGVHD）发生发展的影响。方法用C57BL／6小鼠作为供鼠，BALB／c小鼠作为受鼠，建立小鼠同种allo-BMT模型。BALB／c小鼠随机被分为6组：（1）实验组1：受者经60Co射线照射后输注供者的骨髓细胞与脾细胞，并于移植前第1天，移植后第1、3天分别给受鼠腹腔注射GSI 5μmol／kg；（2）实验组2：受者经。Co射线照射后输注供者的骨髓细胞与脾细胞，并于移植后第1、2、3天分别给受鼠腹腔注射GSI5μmol／妇；（3）移植对照组：受者经。co射线照射后输注供者的骨髓细胞与脾细胞，并分别于移植前第1天和移植后第1、3天给受鼠腹腔注射二甲基亚砜；（4）单纯移植组：受者经60Co射线照射后输注供者的骨髓细胞与脾细胞；（5）单纯照射组：小鼠经60Co射线照射后不进行移植；（6）空白对照组：小鼠未作任何处理。观察各组小鼠的生长情况，监测外周血白细胞数和血小板数，测定移植后第7天时血白细胞介素4（IL-4）和7干扰素（IFN-γ）水平，观察小鼠的肝脏和小肠组织的病理变化。结果实验组1及实验组2的aGVHD发生率分别为60％（6／10）、50％（5／10），均明显低于移植对照组的90％（9／10，P％0．01）。实验组1及实验组2的小鼠存活时间分别为（25．4±3．1）d、（25．2±3．4）d，均明显长于移植对照组的（17．4±2．3）d（P〈0．01）。实验组1及实验组2发生aGVHD的受鼠小肠及肝脏病理改变明显轻于移植对照组。实验组1及实验组2受鼠移植后第7天时的血清IL-4浓度分别为（31．71±1．60）ng／L、（29．27±1．86）ng／L，均高于移植对照组的（23．04±1．82）ng／L（P〈0．01，P〈0．05）；实验组1及实验组2血清IFN-γ浓度分别为（25．97±1．15）ng／L、Objective To investigate the effects and mechanism of Notch signal pathway inhibitor （γ-secretase inhibitor, GSI） on acute graft versus host disease （aGVHD） after allogeneic bone marrow transplantation （allo-BMT）. Method The recipients were BABL/c mice, while the donors were C57BL/6 mice. The murine model of aGVHD had been established by allo-BMT with donor-derived T cells. Experiment was divided into 6 groups： control group （C）, radiation control group （R）, transplantation group （B ＋ S）, transplantation control group （B ＋ S ＋ D）, GSI-1 treated group and GSI-2 treated group. Mice in GSI-1 treated group were daily intraperitoneally injected with GSI （5 mol/kg） （at day l before transplantation and day 1, 3 after transplantation）. Mice in GSI-2 treated group were daily intraperitoneally injected wtih GSI （5 mol/kg） （at day 1, 2, 3 after transplantation）. Result The results showed that the incidence of aGVHD in GSI-1 and GSI-2 treated groups was 60% and 50% respectively, significantly lower than that in transplantation control group （B＋ S＋ D） （90%） （P〈0. 01）. The survival time in GSI-1 and GSI-2 treated groups was 25.40 ± 3. 13 and 25. 20 ± 3. 43 days respectively, significantly longer than that in transplantation control group （17.40± 2. 32 days） （P〈0. 01）, and the aGVHD pathological changes in GSI-1 and GSI-2 treated groups were milder than those in transplantation control group. At 7th day after transplantation, the IL-4 levels in GSI-1 and GSI-2 treated groups were 31.71 ± 1.60 and 29. 27 ± 1.86 ng/L, significantly higher than those in transplantation control group （23.04± 1.82 ng/L） （P〈0. 01, and P〈0. 05 respectively）. The IFN-γ levels in GSI-1 and GSb2 treated groups were 25. 97 ± 1.15 and 22. 69 ± 3.01 ng/L respectively, significantly lower than those in transplantation control group （36. 77 ± 2. 62 ng/L） （P〈0. 01）. Conclusion It is concluded that GSI may alleviate or suppress lethal aGVHD, and elev

关 键 词：小鼠 骨髓移植 移植物抗宿主病 NOTCH信号通路 通路抑制 

分 类 号：R457.7[医药卫生—治疗学]