CTLA4-Ig抗大鼠肝移植排斥反应及诱导免疫耐受的实验研究

Application of Cytotoxic T Lymphocyte Antigen 4 Immunoglobulin G in Prevention of Rejection and the Induction of Immune Tolerance of Orthotopic Liver Transplantation in Rats

目的建立大鼠原位肝移植(ROLT)急性排斥反应模型,探讨细胞毒淋巴细胞抗原4免疫球蛋白(CTLA4-Ig)抗排斥反应和诱导免疫耐受的作用.方法采用'二袖套管'法建立Wistar→SD大鼠配对组合的肝移植后排斥反应模型,并于术后第2天腹腔内一次性注射CTLA4-Ig(75 μg/只大鼠),与未给药的相同组合的排斥反应模型鼠对照研究,观察移植术后7 d 2组动物的一般情况、肝功能变化、移植肝病理改变及血清TNF-α水平的变化,同时观察CTLA4-Ig组动物术后4个月时的上述情况,以了解CTLA4-Ig抗排斥及诱导免疫耐受的作用.结果①对照组动物于肝移植术后6～14 d内相继死亡; 移植肝出现明显的排斥反应的病理改变征象. ②CTLA4-Ig组动物于术后7 d及4个月均未见明显的排斥反应表现,移植肝无明显的排斥反应的病理改变征象,血清TNF-α、ALT、AST、TBIL及DBIL水平均明显低于对照组(P＜0.05),TP及Alb水平则明显高于对照组(P＜0.05).结论 CTLA4-Ig有抗排斥反应及诱导免疫耐受功能的作用; 血清TNF-α水平作为观察ROLT后排斥反应的指标,可能有一定的参考价值.

Objective This study was conducted to build tion in rat （ROLT） with the character of acute rejection; and to experimental model of orthotopic liver transplantastudy the effect of cytotoxic T lymphocyte antigen 4 immunoglobulin G （CTLA4-Ig） on prevention of rejection and the induction of immune tolerance of ROLT. Methods Build model of Wistar→SD ROLT（performed by the two cuff method） with character of acute rejection. Recipients were injected with CTLA4-Ig 75 big per ROLT into abdominal cavity after 2 days of operation. Contrast was made with no treatment group, the clinical characters, the liver function, the transplantated liver pathologic character and the concentrations of TNF-α in serum were observed and measured on postoperative day 7. In treatment group, all above observation were done on postoperative month 4. Above all, determination of the effect of CTLA4-Ig on preventing acute rejection and inducing tolerance in ROLT was observed. Results ORecipients （no treatment group） died one by one within 6th-14th days; pathologic character of rejection in transplantation liver could be found; O In treatment group, on postoperative day 7 and month 4, no clinical rejection character and no pathologic character of rejection in transplantation liver were found and serum concentration of cytokins related to TNF-α found lower than that of contrast group （P〈 0.05 ）, and serum concentration of ALT, AST, TBIL, DBIL found lower too（P〈0.05） ; But serum concentration of TP and Alb was found higher than that of contrast group （P〈0.05）. Conclusion ① CTLA4-Ig treatment alone inhibits the rejection responce in ROLT. ② CTLA4-Ig treatment can Prevent rejection and induce immune tolerance in ROLT model with characters of acute rejection; the serum concentration of cytokins related to TNF-α can probably be used as evaluation standard of rejection in ROLT rejection.