NEUTROPHIL ADHESION AND COMPLEMENT INHIBITION PROLONGS SURVIVAL OF CARDIAC XENOGRAFTS IN DISCORDANT SPECIES

Hyperacute rejection results in rapid destruction of a discordant card iac xenograft and is characterized by antibody deposition, complement activation, nd platelet aggregation. The importance of neutrophils is unclear. Complement inhibition prolongs discordant cardiac xenograft s urvival. The purpose of this experiment was to determine the relative roles of complement and neutrophils. Selective inhibition of complemen t and neutrophil adhesion was used in a guinea pig-to-Lewis rat cardia c heterotopic xenotransplant model. NPC 15669 -dimethylfluorenyl-9-met hoxy)carbonyl]-L-leucine), a member of a new class of antiinflammatory agents termed leumedins, specifically prevents recruitment of neutrop hils at inflammatory foci by inhibiting upregulation of the CD11b/CD18 adhesion molecule. Soluble complement receptor type 1 (sCR1, BRL 5573 0) is a potent inhibitor of the alternative and classical complement p athways. Group I (n=13) received saline vehicle i.v. Group II (n = 15) was treated with NPC 15669 (10 mg/kg i.v. bolus) prior to reperfusion . Group III (n = 13) was treated with sCR1 (20 mg/kg i.v. bolus) prior to reperfusion. Group IV (n=13) received both NPC 15669 and sCR1. Two xenografts were harvested at each interval time point (Groups I and I I, 1, 2,4, and 6 min; and Groups III and IV, 6, 15, 30, and 60 min). T he remainder were followed to cessation of graft function. Graft survi val was significantly increased in group IV and group III-375+/-13.4 m in (mean +/- SD) and 112+/-29.4, respectively (P<.05), compared with 9 .9+/-6.3 in group II and 8.7+/-4.9 in group I. Extreme interstitial he morrhage and edema and contraction band injury were present in group I -III animals at end-stage, and neutrophil infiltration in group III. I n group IV grafts, there was a decrease in these parameters despite th e longer survival time, and at end-stage rejection the cellular infilt rate was primarily mononuclear. This study demonstrates that complemen t is an important mediator in early xenograft HYP injury. Combined tre atment with NPC 15669 and sCR1 results in reduced histologic injury at all time points and longer graft survival than with sCR1 alone. These results suggest that neutrophil and complement activation play synerg istic roles in the pathogenesis of xenograft hyperacute rejection. Neu trophil inhibition may prove to be an important component of multimoda lity therapy for hyperacute rejection, particularly in less-discordant transplants.