PROLONGING DISCORDANT XENOGRAFT SURVIVAL WITH ANTICOMPLEMENT REAGENTSK76COOH AND FUT175

The guinea pig heart, when transplanted into the rat heterotopically, is rejected within 30 min via activation of the alternative complement pathway. Natural antibody does not contribute to rejection. This xeno transplantation model was used to assess the effect of anticomplement reagents on discordant xenograft survival. In vivo administration of K 76COOH (K76) to rats induced only slight suppression of factors B and D and a marked decrease of C3, leading to the depression of ACH50 (ref lecting the potency of the alternative pathway). On the other hand, FU T175 (FUT) reduced C3 activity by about 80%, and inhibited factor B ac tivity nearly 100% <1 hr after the administration, but inhibited facto r D activity only marginally. FUT abrogated ACH50 for >6 hr. Of note, the xenograft, beating time was prolonged approximately 3 times by FUT but not by K76 suggesting that direct inhibition of plasma serine pro tease factor B results in the complete suppression of ACH50 and graft survival. The administration of both K76 and FUT resulted in the longe st graft survival, but the effects of these reagents were abolished by additional antigraft antibody. Anticomplement reagents that block fac tor B and C3 are therefore effective for prolongation of discordant xe nograft survival when the graft rejection is associated with the compl ement alternative pathway.