Successful conversion from conventional immunosuppression to anti-CD154 monoclonal antibody costimulatory molecule blockade in rhesus renal allograftrecipients

Background. Several conventional forms of nosuppression. have been shown to antagonize the efficacy of anti-CD154 monoclonal antibody- (mAb) based cos timulatory molecule blockade immunotherapy. Our objective was to determine if allograft recipients treated with a conventional immunosuppressive regim en could be sequentially converted to anti-CD154 mAb monotherapy without co mpromising graft survival. Methods. Outbred juvenile rhesus monkeys underwent renal allotransplantatio n from MHC-disparate donors. After a 60-day course of triple therapy immuno suppression. with steroids, cyclosporine, and mycophenolate mofetil, monkey s were treated with: (1) cessation of all immunosuppression (control); (2) seven monthly doses of 20 mg/kg hu5C8 (maintenance), or; (3) 20 mg/kg hu5C8 on posttransplant days 60, 61, 64, 71, 79, and 88 followed by five monthly doses (induction+maintenance). Graft rejection was defined by elevation in serum creatinine >1.5 mg/dl combined with histologic evidence of rejection . Results. Graft survival for the three groups were as follows: group I (cont rol): 70, 75, > 279 days; group 2 (maintenance): 83, 349, > 293 days, and; group 3 (induction+ maintenance): 355, > 377, > 314 days. Acute rejection d eveloping in two of four monkeys after treatment with conventional immunosu ppression was successfully reversed with intensive hu5CS monotherapy. Conclusions. Renal allograft recipients can be successfully converted to CD 154 blockade monotherapy after 60 days of conventional immunosuppression. A n induction phase of anti-CD154 mAb appears to be necessary for optimal con version. Therefore, although concurrent administration of conventional immu nosuppressive agents including steroids and calcineurin inhibitors has been shown to inhibit the efficacy of CD154 blockade, sequential conversion fro m these agents to CD154 blockade appears to be effective.