Evidence for an involvement of the neutrophil integrin lymphocyte function-associated antigen-1 in early failure of heart transplants

Academic Article

Abstract

  • Background: The adhesion of neutrophils to the coronary vascular wall contributes to reperfusion injury of cardiac allografts. This phenomenon involves interactions between neutrophil β2-integrins (CD11a/CD18 [lymphocyte function associated antigen-1, or LFA-1], CD11b/CD18 [membrane attack complex-1, or MAC-1], and CD11c/CD18 [p150,95]) and their endothelial ligands. Whereas the roles of the common β-chain (CD18) and of the α- subunit of MAC-1 (CD11b) have been studied extensively, the role of the α subunit of LFA-1 (CD11a) remains less well defined. The objective of this study, therefore, was to assess the effects of CD11a blockade on postischemic function and neutrophil infiltration of cardiac allografts. Methods and Results: Twenty-six rat hearts were kept in cold storage for 4 hours, heterotopically transplanted in the abdomen of recipient rats, and reperfused for 1 hour. In 10 hearts, a monoclonal antibody against LFA-1α was given as a single intravenous bolus (100 μg) 35 minutes before reperfusion. The control groups consisted of 10 hearts that received saline and 6 hearts treated with an isotype-matched, nonbinding antibody (OKT3) administered at the same dosage and schedule as in the anti-LFA-1α group. Before reperfusion, all hearts were instrumented with an intraventricular balloon tipped catheter to allow serial isovolumic measurements of left ventricular function during reperfusion, after which myocardial accumulation of neutrophils was measured by myeloperoxidase activity. Postischemic heart rate and diastolic pressure were comparable among groups. However, the best recovery of contractility was achieved with anti-LFA-1α treatment. After 60 minutes of reperfusion, dP/dt values were 1680±66 mmHg/s-1, 1733±25 mmHg/s-1, and 2550±95 mm Hg/s-1 in the saline, OKT3, and anti-LFA-1α groups, respectively (P<.0001 between anti-LFA-1α and the two control groups). This correlated with a significant (P<.0001) reduction in myocardial accumulation of neutrophils in the anti-LFA-1α group (3.3±0.1 versus 7.9±0.6 and 6.7+0.3 U/100) mg tissue in the saline and OKT3 groups, respectively). Conclusions: These results suggest the involvement of the α- subunit of LFA-1 (CD11a) in neutrophil mediated reperfusion injury incurred by transplanted hearts. This finding is clinically relevant in view of the recent development of an anti-LFA-1α monoclonal antibody for human use, the cardioprotective effects of which might thus extend beyond the initially intended prevention of lymphocyte-mediated rejection.
  • Published In

  • Circulation  Journal
  • Author List

  • Oubenaissa A; Mouas C; Bourgeois F; Le Deist F; Albérici G; Moalic JM; Menasché P
  • Volume

  • 94
  • Issue

  • 9 SUPPL.