Significant prolongation of renal allograft survival by delayed combination therapy of FK778 with tacrolimus in non human primates / 中华器官移植杂志

ABSTRACT

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 not on T cells.