THE EFFECT OF SOLUBLE COMPLEMENT RECEPTOR-TYPE-1 ON HYPERACUTE REJECTION OF PORCINE XENOGRAFTS

The use of xenografts (Xgs) from distantly related species to relieve the increasing shortage of organs for clinical transplantation is prev ented by the occurrence of hyperacute rejection (HAR). This process, i n which C activation plays a central role, cannot be inhibited with cu rrently available immunosuppressants. In two clinically relevant xenot ransplantation models, this study evaluated the effect of C inhibition using recombinant soluble complement receptor type 1 (sCR1) on HAR. I n an ex vivo model in which porcine cardiac Xgs were perfused with hum an blood, cardiac function ceased within 34 min when the perfusate blo od was untreated (n=3). When the perfusate blood was treated with sCR1 (300 mu g/ml), cardiac Xg function was maintained for up to 4 hr (n=3 ). Immunohistologic examination of these Xgs demonstrated deposition o f C3b/iC3b and C3d in Xgs perfused with untreated human blood but only C3d deposition in those Xgs perfused with sCR1-treated human blood. T hese findings are consistent with the cofactor activity of sCR1 for fa ctor I-mediated degradation of deposited C3b/iC3b to C3d. Treatment wi th sCR1 also prevented the histopathologic changes of HAR observed whe n untreated blood was used as the perfusate. In an in vivo pig-to-prim ate heterotopic cardiac xenotransplantation model, in which porcine Xg s transplanted into untreated cynomolgus monkey recipients underwent H AR in I hr or less (n=3), a single intravenous bolus of sCR1 (15 mg/kg ) administered to the recipient immediately before Xg reperfusion mark edly inhibited total and alternative pathway serum C activity and prol onged Xg survival to between 48 and 90 hr (n=5). These studies confirm the important role of C activation in HAR of porcine cardiac Xgs by p rimates and indicate that sCR1 may be a useful agent for xenotransplan tation.