INHIBITION OF NEUTROPHIL ADHESION AND THE MEMBRANE ATTACK COMPLEX OF COMPLEMENT SYNERGISTICALLY PROLONGS CARDIAC XENOGRAFT SURVIVAL

Background: Hyperacute xenograft rejection is affected by activation o f the complement cascade. Split products of early complement component s influence the localization, activation, and effector function of pla telets, granulocytes, monocytes, and lymphocytes, whereas the formatio n of the membrane attack complex (C5b-9) leads to direct cellular inju ry. In a unique strain of PVG rats deficient in the C6 component of co mplement, the terminal membrane attack complex is not formed. However, production of the chemotactic and vasoactive components C3a and C5a p roceeds normally. Guinea pig cardiac xenografts in these C6-deficient rats have prolonged survival, and at the time of rejection the inflamm atory infiltrate is composed primarily of neutrophils. NPC 15669, a me mber of a class of antiinflammatory agents called leumedins, is known to inhibit neutrophil adhesion. The purpose of this study was to deter mine whether inhibition of neutrophil recruitment in animals incapable of membrane attack complex formation would prolong cardiac xenograft survival. Methods: Cardiac xenografts from male Hartley guinea pigs we re heterotopically grafted into PVG (C-) and PVG (C+) male rats. Exper imental animals received 20 mg/kg of NPC 15669 IV before crossclamp re lease and 10 mg/kg of NPC 15669 intravenously on postoperative day 1. Control animals received intravenous saline solution only. Results: Co mplement sufficient PVG (C+) rats rejected cardiac xenografts hyperacu tely despite mode of treatment: PVG (CS) rats which received saline so lution (n = 5) rejected their xenografts at 10.8 +/- 2.6 minutes, and those receiving NPC 15669 (n = 5) rejected at 13.9 +/- 5.3 minutes. Hi stologic examination showed edema, platelet aggregation, and hemorrhag e but no cellular inflammatory infiltrate. As expected, complement-def icient PVG (C-) rats had markedly longer xenograft survival in the sal ine solution-treated group (n = 5) with graft function being sustained 14.7 +/- 6.1 hours. NPC 15669 treatment (n = 4) further prolonged gra ft function to 61.0 +/- 4.7 hours. In addition to edema, platelet aggr egation, and hemorrhage, histologic analysis of these grafts at the ti me of rejection was characterized by an infiltration of neutrophils. C onclusions: We conclude that neutrophils play a critical role in cardi ac xenograft rejection when complement activation is restricted. Combi ned inhibition of complement and neutrophil adhesion prolongs xenograf t survival longer than inhibition of either component alone.