他克莫司与新型免疫抑制剂FK778联合应用预防肾移植急性排斥反应的实验  

Significant prolongation of renal allograft survival by delayed combination therapy of FK778 with tacrolimus in non human primates

作　　者：欧阳骏[1] 严春寅[1] 温端改[1] 朱生云[2] 王翔[2] 徐大生[2] 齐世杰[2] 马安伦[2] 蒋文雷[2] 陈惠方[2] 

机构地区：[1]苏州大学附属第一医院泌尿外科,江苏215006 [2]加拿大蒙特利尔大学Notre-Dame医院实验外科器官移植中心

出　　处：《中华器官移植杂志》2004年第5期260-263,共4页Chinese Journal of Organ Transplantation

摘　　要：目的评价FK778与他克莫司(FK506)联合应用预防猴同种异体肾移植急性排斥反应的效果。方法Vervet猴同种异体肾移植后联合应用FK506和FK778预防急性排斥反应,给药60d,同时进行T、B淋巴细胞增殖抑制实验。结果术后同一时间开始使用FK506和FK778者,其移植肾存活时间与单独用药组比较,差异无显著性;若FK778较FK506延迟1周给予,则移植肾的存活时间明显延长;FK778与FK506联合应用,在体外对B淋巴细胞增殖的抑制作用具有协同效应,而在抑制T淋巴细胞增殖时存在拮抗倾向。结论FK506、FK778均有很强的免疫抑制效应,联合应用时以FK778延迟1周应用效果较佳。Objective To investigate the effectiveness of malononitrilamide 715 (FK778) in combination with tacrolimus in prevention of acute renal allograft rejection in Vervet monkeys. Methods Eleven groups ( n ≥4/group) were involved in this study. FK778 and tacrolimus were administered orally for 60 days according to protocol. Proliferation assay was used to evaluate the effect of FK778 plus tacrolimus on monkey lymphocytes, after activation with T or B cell specific mitogens. Results Naive controls rejected renal graft with a median survival time (MST) of 8.0 days in group 1. When recipient monkeys were treated with tacrolimus 1.0 mg·kg -1 ·d -1 in group 2 or FK778 2.5 mg·kg -1 ·d -1 in group 3, the MST was 16.0 days ( P = 0.001 ) and 11.0 days ( P = 0.266 ), respectively. Combination therapy of these two agents at the same doses immediately after transplantation resulted in a MST of 25.0 days ( P = 0.016 ) in group 4. When tacrolimus was initiated immediately after transplantation and FK778 treatment was delayed until day 7 after surgery in group 5, recipient survivals were significantly prolonged to 38.0 days ( P = 0.02 ). These results were repeatable when FK778 5.0 mg·kg -1 ·d -1 ( 9.0 days, P = 0.544 in group 6) was combined with tacrolimus 1.0 mg·kg -1 ·d -1 immediately after transplantation ( 8.0 days, P = 0.339 ) in group 7, or when FK778 was delayed 7 days ( 60.0 days, P = 0.002 ) in group 8. Furthermore, it was also repeatable when FK778 10 mg·kg -1 ·d -1 was combined with tacrolimus 1.0 mg·kg -1 ·d -1 with a 7 day delay. Proliferation assay in the combination groups revealed that 88.8 % (8/9) produced additive to synergistic effects in B cells, while 66.6 % (6/9) produced moderate antagonistic effects in T cells. Conclusion A significant prolongation of renal allograft survival was produced when FK778 administration was delayed by 7 days combined with tacrolimus in Vervet monkeys. And the combination of FK778 with tacrolimus in vitro produces synergistic inhibition on B cells proliferation, but

关 键 词：联合应用 急性排斥反应 FK506 他克莫司 预防 FKS06 同种异体肾移植 结论 实验 倾向 

分 类 号：R699.2[医药卫生—泌尿科学] R979.5[医药卫生—外科学]