The study investigates the use of CTLA4-Ig and anti-CD40 ligand (CD40L) antibodies to prevent renal allograft rejection in rhesus monkeys. Both agents were found to inhibit rhesus mixed lymphocyte reactions (MLRs) effectively, with the combination being 100 times more potent than either drug alone. In a preclinical model, renal allografts were transplanted into nephrectomized rhesus monkeys with disparate major histocompatibility complex (MHC) class I and II loci. Control animals rejected within 5-8 days, while brief induction doses of CTLA4-Ig or 5C8 alone significantly prolonged rejection-free survival (20-98 days). Two out of four animals treated with both agents experienced extended (over 150 days) rejection-free allograft survival. Two animals treated with 5C8 alone and one with both 5C8 and CTLA4-Ig experienced late, biopsy-proven rejection but were successfully restored to normal graft function with a repeat course of their induction regimen. Neither drug affected peripheral T cell or B cell counts, and there were no clinically evident side effects or rejections during treatment. The findings suggest that CTLA4-Ig and 5C8 can prevent and reverse acute allograft rejection, significantly prolonging the survival of major histocompatibility complex-mismatched renal allografts in primates without the need for chronic immunosuppression.The study investigates the use of CTLA4-Ig and anti-CD40 ligand (CD40L) antibodies to prevent renal allograft rejection in rhesus monkeys. Both agents were found to inhibit rhesus mixed lymphocyte reactions (MLRs) effectively, with the combination being 100 times more potent than either drug alone. In a preclinical model, renal allografts were transplanted into nephrectomized rhesus monkeys with disparate major histocompatibility complex (MHC) class I and II loci. Control animals rejected within 5-8 days, while brief induction doses of CTLA4-Ig or 5C8 alone significantly prolonged rejection-free survival (20-98 days). Two out of four animals treated with both agents experienced extended (over 150 days) rejection-free allograft survival. Two animals treated with 5C8 alone and one with both 5C8 and CTLA4-Ig experienced late, biopsy-proven rejection but were successfully restored to normal graft function with a repeat course of their induction regimen. Neither drug affected peripheral T cell or B cell counts, and there were no clinically evident side effects or rejections during treatment. The findings suggest that CTLA4-Ig and 5C8 can prevent and reverse acute allograft rejection, significantly prolonging the survival of major histocompatibility complex-mismatched renal allografts in primates without the need for chronic immunosuppression.