NEUTROPHIL ADHESION INHIBITION PROLONGS SURVIVAL OF CARDIAC ALLOGRAFTS WITH HYPERACUTE REJECTION

Hyperacute rejection results in rapid destruction of a cardiac allogra ft and is characterized by infiltration of neutrophils into the donor organ. We sought to ameliorate this response by using a potent inhibit or 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 speci fically prevents recruitment of neutrophils at inflammatory foci by in hibiting upregulation of the CD11b/CD18 adhesion molecule located on t he neutrophil surface. Lewis rats were presensitized by three serial A CI rat skin grafts placed 10 days apart. ACI rat hearts were heterotop ically transplanted into Lewis recipients 10 to 14 days after the fina l 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 mi nutes. Group II (n = 13) was given saline vehicle intravenously. Two a llografts in each group were harvested at 5, 15, 30, and 60 minutes, a nd the remainder were followed to cessation of graft function. Early 5 - to 60-minute allograft histologic findings revealed focal interstiti al hemorrhage, edema, and contraction-band necrosis associated with ne utrophil infiltration in group II. Group I had significant reduction o f all parameters at the earliest time points. Graft survival was signi ficantly increased in group I, 89.2 +/- 20.3 hours (mean +/- SD) compa red to 27 +/- 17 hours in group II (p < 0.0001). End-stage rejection w as characterized by extensive neutrophil infiltrate and hemorrhage in group II; group I grafts had a predominantly mononuclear cell infiltra te with rare neutrophils. This study shows that treatment of hyperacut e rejection with NPC 15669 results in (1) significant prolongation of graft survival, (2) marked reduction in neutrophil infiltration and as sociated 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 i n hyperacute rejection. Inhibition of the neutrophil-mediated hyperacu te rejection injury may clinically improve xenograft survival.