title: Neutrophil adhesion and complement inhibition prolongs survival of cardiac xenografts in discordant species.
abstract: Hyperacute rejection results in rapid destruction of a discordant cardiac xenograft and is characterized by antibody deposition, complement activation, and platelet aggregation. The importance of neutrophils is unclear. Complement inhibition prolongs discordant cardiac xenograft survival. The purpose of this experiment was to determine the relative roles of complement and neutrophils. Selective inhibition of complement and neutrophil adhesion was used in a guinea pig-to-Lewis rat cardiac heterotopic xenotransplant model. NPC 15669 (N-[9H-(2,7-dimethylfluorenyl-9-methoxy)carbonyl]-L-leucine), a member of a new class of antiinflammatory agents termed leumedins, specifically prevents recruitment of neutrophils at inflammatory foci by inhibiting upregulation of the CD11b/CD18 adhesion molecule. Soluble complement receptor type 1 (sCR1, BRL 55730) is a potent inhibitor of the alternative and classical complement pathways. 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 II, 1, 2, 4, and 6 min; and Groups III and IV, 6, 15, 30, and 60 min). The remainder were followed to cessation of graft function. Graft survival was significantly increased in group IV and group III-375 +/- 13.4 min (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 hemorrhage and edema and contraction band injury were present in group I-III animals at end-stage, and neutrophil infiltration in group III. In group IV grafts, there was a decrease in these parameters despite the longer survival time, and at end-stage rejection the cellular infiltrate was primarily mononuclear. This study demonstrates that complement is an important mediator in early xenograft HYP injury. Combined treatment 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 synergistic roles in the pathogenesis of xenograft hyperacute rejection. Neutrophil inhibition may prove to be an important component of multimodality therapy for hyperacute rejection, particularly in less-discordant transplants.
authors.affiliation: Division of Cardiac Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287.
authors.forename: K J
authors.initials: KJ
authors.lastname: Zehr
authors.forename: A
authors.initials: A
authors.lastname: Herskowitz
authors.forename: P C
authors.initials: PC
authors.lastname: Lee
authors.forename: P
authors.initials: P
authors.lastname: Kumar
authors.forename: A M
authors.initials: AM
authors.lastname: Gillinov
authors.forename: W A
authors.initials: WA
authors.lastname: Baumgartner
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002448:Cell Adhesion; D003169:Complement Inactivator Proteins / Q000494:pharmacology*; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D006168:Guinea Pigs; D016027:Heart Transplantation / Q000276:immunology*; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology*; D051381:Rats; D011917:Rats, Inbred Lew; D011951:Receptors, Complement / Q000502:physiology; D012995:Solubility; D014183:Transplantation, Heterologous / Q000276:immunology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003169:Complement Inactivator Proteins; D011951:Receptors, Complement; C071244:N-(9H-(2,7-dimethylfluoren-9-ylmethoxy)carbonyl)leucine; D007930:Leucine