EFFECT OF REPETITIVE HIGH-DOSE TREATMENT WITH SOLUBLE COMPLEMENT RECEPTOR-TYPE-1 AND COBRA VENOM FACTOR ON DISCORDANT XENOGRAFT SURVIVAL

Hyperacute xenograft rejection may be modified by the activation and d epletion of complement (C) using cobra venom factor (CVF). This method of prolonging xenograft survival is toxic and associated with systemi c inflammation, which may potentially contribute to the pathologic fea tures of delayed xenograft rejection. Soluble complement receptor type 1 (sCR1) inhibits both the classical and alternative C pathways and t hus limits the production of proinflammatory products such as the anap hylatoxins. Hence, we investigated the effects of various sCR1 and CVF regimens, and combinations thereof, in the discordant guinea pig-to-L ewis rat cardiac xenograft model. Mean graft survival time (MST) was s ignificantly prolonged with repetitive dosing (MST=22 hr) or continuou s infusion of sCR1 (MST=32 hr) as compared with unmodified controls (M ST=15 min). However, sCR1 did not prevent intragraft deposition of C3 or neutrophil infiltration and resulted in only partial inhibition of C-mediated hemolytic activity in vitro. Grafts in rats treated with a single dose of CVF (MST=67 hr) or repetitive doses of CVF (MST=69 hr) survived significantly longer than those treated with sCR1 alone, and lacked C3 deposition or neutrophil accumulation. Sera from these anima ls were completely depleted of C-mediated hemolytic activity. Animals treated with a single dose of CVF, or sCR1 plus a single dose of CVF ( MST=64 hr), had similar xenograft survival times. However, immuno-hist ologic studies showed that addition of sCR1 to a single dose of CVF re sulted in decreased macrophage activation and reduced levels of cytoki nes (tumor necrosis factor-alpha and interleukin-1 beta) within xenogr afts as compared with that in recipients treated with CVF alone. Such decreased macrophage activation may result from the binding of C4b by sCR1, since combination therapy may augment further therapeutic manipu lations to achieve discordant xenograft survival without the attendant toxicity associated with repeated CVF administration.