Neutrophil adhesion inhibition prolongs survival of cardiac allografts with hyperacute rejection

K. J. Zehr, A. Herskowitz, P. C. Lee, R. S. Poston, A. M. Gillinov, W. A. Baumgartner

Research output: Contribution to journalArticle

Abstract

Hyperacute rejection results in rapid destruction of a cardiac allograft and is characterized by infiltration of neutrophils into the donor organ. We sought to ameliorate this response by using a potent inhibitor of neutrophil adhesion to vascular endothelium, NPC 15669 (N-[9H-(2,7-dimethylfluorenyl-9- methoxy) carbonyl]-L-leucine) and determine its effect on long-term graft survival and histology. This compound specifically prevents recruitment of neutrophils at inflammatory foci by inhibiting upregulation of the CD11b/CD18 adhesion molecule located on the neutrophil surface. Lewis rats were presensitized by three serial ACI rat skin grafts placed 10 days apart. ACI rat hearts were heterotopically transplanted into Lewis recipients 10 to 14 days after the final skin graft. Group I (n = 15) was treated with a 10 mg/kg intravenous bolus of NPC 15669 before reperfusion, followed by 3 mg/kg over 30 minutes. Group II (n = 13) was given saline vehicle intravenously. Two allografts in each group were harvested at 5, 15, 30, and 60 minutes, and the remainder were followed to cessation of graft function. Early 5- to 60- minute allograft histologic findings revealed focal interstitial hemorrhage, edema, and contraction-band necrosis associated with neutrophil infiltration in group II. Group I had significant reduction of all parameters at the earliest time points. Graft survival was significantly increased in group I, 89.2 ± 20.3 hours (mean ± SD) compared to 27 ± 17 hours in group II (p < 0.0001). End-stage rejection was characterized by extensive neutrophil infiltrate and hemorrhage in group II; group I grafts had a predominantly mononuclear cell infiltrate with rare neutrophils. This study shows that treatment of hyperacute rejection with NPC 15669 results in (1) significant prolongation of graft survival, (2) marked reduction in neutrophil infiltration and associated cellular damage at early time points, and (3) modification of end-stage rejection to a primarily mononuclear immune response. These results support the hypothesis that neutrophils play a primary role in hyperacute rejection. Inhibition of the neutrophil-mediated hyperacute rejection injury may clinically improve xenograft survival.

Original languageEnglish (US)
Pages (from-to)837-845
Number of pages9
JournalJournal of Heart and Lung Transplantation
Volume12
Issue number5
StatePublished - Jan 1 1993

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

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