FK506和CTLA4Ig转基因腺病毒在耐受诱导中的作用

The effect of FK506 and adenovirus containing CTLA4Ig gene on the induction of transplantation tolerance

目的 评价Tacrolimus(FK5 0 6 )和细胞毒性T淋巴相关抗原4免疫球蛋白(CTLA4Ig)转基因腺病毒(AdCTLA4Ig)在耐受诱导中的作用。方法 按照是否接受FK5 0 6处理、心脏移植后有无骨髓细胞输注(bonemarrowtransfusion ,BMT)、术后有无AdCTLA4Ig输注及移植心脏来源,将实验动物随机分为8组,观察各组心脏移植物的存活时间,于术后第30天测定其中4组的混合淋巴细胞反应的特异性和非特异性抑制率以及其中4组的异基因嵌合水平。结果 无处理对照组移植心脏存活时间为(6 .5±0 .5 5 )d ;AdCTLA4Ig单一处理组及联合BMT组移植心脏存活时间分别为(37.5±2 .88)d和(39.2±3.31)d ,与无处理组比较,差异有统计学意义(P <0 .0 5 ) ,当把FK5 0 6处理加入到上述2组的处理方案中时,移植心脏存活时间缩短(P <0 .0 5 )。术后30d混合淋巴细胞反应(MLR)结果显示,AdCTLA4Ig +BMT组和AdCTLA4Ig组的特异性抑制率明显高于FK5 0 6 +AdCTLA4Ig +BMT组和FK5 0 6+AdCTLA4Ig组(P <0 .0 5 ) ,而非特异性抑制率并没有差别。术后30d的异基因嵌合水平检测显示,BMT +AdCTLA4Ig组的胸腺和外周血嵌合水平高于AdlacZ腺病毒组、无处理对照组和AdCTLA4Ig组(P <0 .0 5 )。结论 在耐受诱导过程中,当FK5 0 6和AdCTLA4Ig联合应用时,前者会对后者的作用产?

Objective To evaluate the effect of Tacrolimus a nd AdCTLA4Ig on the induction of transplantation tolerance. Methods The recipients were randomly divided into 8 groups according to the t reatment. Graft survival was observed. Mixed lymphocyte reaction of recipients′ lymphocyte to inactivated donors′ and third party′s lymphocyte was performed 30 days after cardiac transplantation. The degree of chimerism of peripheral lym phocyte and thymocyte was detected 30 days after cardiac transplantation. Results Survival of cardiac allografts in groups treated with AdCTLA4Ig or AdCTLA4Ig+BMT were significantly prolonged, as compared with untrea ted group (37.5±2.88 days, 39.2±3.31 days vs 6.5±0.55 days, P<0.05). When FK506 was added to the regimens containing AdCTLA4Ig, survival of cardiac allog rafts was significantly shortened (P<0.05). MLR results of groups treated wi th BMT+AdCTLA4Ig or AdCTLA4Ig demonstrated donor-specific hyporesponsiveness an d normal responsiveness to third party′s antigen, while MLR results of groups t reated with FK506+AdCTLA4Ig+BMT or FK506+AdCTLA4Ig did not demonstrate donor spe cific hyporesponsiveness. The degree of chimerism was higher in group treated wi th BMT+AdCTLA4Ig than the degree in untreated group, AdCTLA4Ig-treated group an d AdlacZ-treated group (P<0.05). Conclusion When CTL A4Ig is combined with FK506 in the process of tolerance induction, the latter ca n antagonize the effect of the former. The effect of CTLA4Ig′s prolonging survi val of cardiac allografts has nothing to do with macrochimerism.