趋化因子受体拮抗剂对大鼠小肠移植的影响(英文)

Effect of chemokine receptor antagonist on small intestine transplantation in rats

背景:排斥反应的发生是导致小肠移植失败的主要原因,趋化因子及其受体介导的细胞免疫在急性排斥反应中具有重要作用,以趋化因子受体为靶位的治疗方案,可能为临床小肠移植的免疫治疗提供借鉴。目的:观察趋化因子RANTES(Met-RANTES)对同种异体大鼠异位小肠移植术后移植物的存活时间和组织病理学改变的影响,以及与小剂量他克莫司的协同效应。设计、时间及地点:随机数字表法区组,对照观察实验,于2003-09/2005-03在解放军第四军医大学西京医院胃肠外科实验室完成。材料:健康成年雄性大鼠180只,90只SD大鼠作为供体,90只Wistar大鼠作为受体,施行异位节段性小肠移植。方法:小肠移植后,大鼠随机分为3组,30只/组:对照组,只做异位小肠移植,不给予任何药物治疗,Met-RANTES治疗组:移植后0～7d,腹腔注射Met-RANTES200μg/d;Met-RANTES联合小剂量他克莫司治疗组:移植后0～7d,腹腔注射Met-RANTES200μg/d+肌肉注射他克莫司0.5mg/(kg·d)。主要观察指标:观察移植大鼠的一般状况和存活时间,并于移植后第1,3,5,7天每组各处死6只大鼠,切取移植肠标本进行组织病理学检查和组间比较。结果:移植后的90只受体大鼠全部进入结果分析。对照组大鼠存活时间中位数为7.2d(1.5),全部死于急性排斥反应及感染。组织病理学检查显示移植后第3,5,7天分别符合轻、中、重度排斥反应。Met-RANTES治疗组大鼠存活时间中位数为19.2d(16.4),与对照组相比存活时间明显延长(P<0.01)。Met-RANTES+小剂量他克莫司治疗组大鼠存活时间中位数为30.9d(9.0),与前两组有显著差异(P<0.01)。Met-RANTES治疗组和Met-RANTES+小剂量他克莫司治疗组大鼠组织病理学检查无明显排斥反应征象,可长期存活。结论:Met-RANTES能明显抑制小肠移植急性排斥反应,有效保护移植肠功能,显著延长移植物的存活时间,并可增强小剂量他克莫司的免疫抑制作用。

BACKGROUND： Rejection is the main cause of the failure in small intestine transplantation. Cellular immunity mediated by chemotatic factor and the receptor plays an important role in acute rejection. We regard chemokine receptor as target site to design the treatment, which may provide reference for the immunotherapy in clinical small intestine transplantation. OBJECTIVE： To observe the effect of chemokine receptor antagonist, regulated upon activation, normal T cell expressed and secreted （Met-RANTES）, on the survival time and histopathological changes of allograft rats which have received heterotopic small intestine transplantation, and the coordinative effects of Met-RANTES used together with low-dose tacrolimus. DESIGN, TIME AND SETTING： Randomized complete-block design and controlled animal experiment, performed in the Department of Gastrointestinal Surgery, Xijing Hospital, the Fourth Military Medical University of Chinese PLA between September 2003 and March 2005. MATERIALS： 180 healthy adult male rats including 90 rats （donors） and 90 Wistar rats （recipients） were involved in this study. Heterotopic segmental small intestine transplantation was performed. METHODS： The rats were randomly divided into 3 groups with 30 rats for each group. Control group： Rats were treated with heterotopic small intestine transplantation alone; Met-RANTES group： Rats were treated with an intraperitoneal injection of Met-RANTES （200μg/d） at 0-7 days after transplantation; Met-RANTES ＋ low-dose FK506 group： Rats were treated with an intraperitoneal injection of Met-RANTES （200 μg/d） ＋ tacrolimus （0.5 mg/kg/d） at 0-7 days after transplantation. MAIN OUTCOME MEASURES： Gross status and survival time were detected; in addition, every 6 rats were sacrificed at different time points, such as 1,3, 5, and 7 days after transplantation, to compare histopathological changes. RESULTS： Following transplantation, 90 Wistar rats （recipients） were all involved in the final analysis. The survival time median in the control group was 7.2 days （1.5）, and all rats died of acute rejection and infection. Histopathological examination showed that mild, moderate and severe rejections were detected at day 3, 5, and 7 after transplantation, respectively. The survival time median in the Met-RANTES group was 19.2 days （16.4）, which was significantly longer than the control group （P 〈 0.01）. The survival time median in the Met-RANTES ＋ low-dose tacrolimus group was 30.9 days （9.0）, and there were significant differences in survival rate as compared with control group and Met-RANTES group （P〈 0.01）. While the rats in the Met-RANTES group and the Met-RANTES ＋ low-dose tacrolimus group showed no obvious indication of rejection. CONCLUSION： Met-RANTES may obviously inhibit acute rejection following small intestine transplantation, effectively protect the function of grafts, and significantly prolong the survival time of the recipients. In addition, Met-RANTES may enhance the immunosuppressive function of low-dose tacrolimus.