EFFECT OF ANTICOMPLEMENT AGENT K76 COOH ON HAMSTER-TO-RAT AND GUINEA PIG-TO-RAT HEART XENOTRANSPLANTATION

In normal rats, the xenobiotic K76 inhibited the C5 and probably the C 2 and C3 steps of complement and effectively depressed classical compl ement pathway activity, alternative complement pathway activity, and t he C3 complement component during and well beyond the drug's 3-hr half -life, It was tested alone and with intramuscular tacrolimus (TAC) and /or intragastric cyclophosphamide (CP) in rat recipients of heterotopi c hearts from guinea pig (discordant) and hamster (concordant) donors, Single prevascularization doses of 100 and 200 mg/kg increased the me dian survival time of guinea pig hearts from 0.17 hr in untreated cont rols to 1.7 hr and 10.2 hr, respectively; with repeated injections of the 200-mg dose every 9-12 hr, graft survival time was increased to 18 .1 hr, Pretreatment of guinea pig heart recipients for 10 days with TA C and CP, with or without perioperative splenectomy or infusion of don or bone marrow, further increased median graft survival time to 24 hr, Among the guinea pig recipients, the majority of treated animals died with a beating heart from respiratory failure that was ascribed to an aphylatoxins. Hamster heart survival also was increased with monothera py using 200 mg/kg b.i.d. i.v. K76 (limited by protocol to 6 days), bu t only from 3 to 4 days, Survival was prolonged to 7 days with the add ition to K76 of intragastric CP at 5 mg/kg per day begun 1 day before operation (to a limit of 9 days); it was prolonged to 4.5 days with th e addition of intramuscular TAC at 2 mg/kg per day beginning on the da y of transplantation and continued indefinitely, In contrast to the li mited efficacy of the single drugs, or any two drugs in combination, t he three drugs together (K76, CP, and TAC) in the same dose schedules increased median graft survival time to 61 days, Antihamster antibodie s rapidly increased during the first 5 days after transplantation, and plateaued at an abnormal level in animals with long graft survival ti mes without immediate humoral rejection, However, rejection could not be reliably prevented, and was present even in most of the xenografts recovered from most of the animals dying (usually from infection) with a beating heart. Thus, although effective complement inhibition with K76 was achieved in both guinea pig- and hamster-to-rat heart transpla nt models, the results suggest that effective interruption of the comp lement cascade will have a limited role, if any, in the induction of x enograft acceptance.