EVIDENCE FOR AN INVOLVEMENT OF THE NEUTROPHIL INTEGRIN LYMPHOCYTE FUNCTION-ASSOCIATED ANTIGEN-1 IN EARLY FAILURE OF HEART-TRANSPLANTS

Background The adhesion of neutrophils to the coronary vascular wall c ontributes to reperfusion injury of cardiac allografts. This phenomeno n involves interactions between neutrophil beta(2)-integrins (CD11a/CD 18 [lymphocyte function-associated antigen-1, or LFA-1], CD11b/CD18 [m embrane attack complex-1, or MAC-1], and CD11c/CD18 [p150,95]) and the ir endothelial ligands. Whereas the roles of the common beta-chain (CD 18) and of the alpha-subunit of MAC-1 (CD11b) have been studied extens ively, the role of the alpha-subunit of LFA-1 (CD11a) remains less wel l defined. The objective of this study, therefore, was to assess the e ffects of CD11a blockade on postischemic function and neutrophil infil tration of cardiac allografts. Methods and Results Twenty-six rat hear ts were kept in cold storage for 4 hours, heterotopically transplanted in the abdomen of recipient rats, and reperfused for 1 hour. In 10 he arts, a monoclonal antibody against LFA-1 alpha was given as a single intravenous bolus (100 mu g) 35 minutes before reperfusion. The contro l groups consisted of 10 hearts that received saline and 6 hearts trea ted with an isotype-matched, nonbinding antibody (OKT3) administered a t the same dosage and schedule as in the anti-LFA-1 alpha group. Befor e reperfusion, all hearts were instrumented with an intraventricular b alloon-tipped catheter to allow serial isovolumic measurements of left ventricular function during reperfusion, after which myocardial accum ulation of neutrophils was measured by myeloperoxidase activity. Posti schemic heart rate and diastolic pressure were comparable among groups . However, the best recovery of contractility was achieved with anti-L FA-1 alpha treatment. After 60 minutes of reperfusion, dP/dt values we re 1680+/-66 mm Hg/s(-1), 1733+/-25 mm Hg/s(-1), and 2550+/-95 mm Hg/s (-1) in the saline, OKT3, and anti-LFA-1 alpha groups, respectively (P <.0001 between anti-LFA-1 alpha and the two control groups). This corr elated with a significant (P<.0001) reduction in myocardial accumulati on of neutrophils in the anti-LFA-1 alpha 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, res pectively). Conclusions These results suggest the involvement of the a lpha-subunit of LFA-1 (CD11a) in neutrophil-mediated reperfusion injur y incurred by transplanted hearts. This finding is clinically relevant in view of the recent development of an anti-LFA-1 alpha monoclonal a ntibody for human use, the cardioprotective effects of which might thu s extend beyond the initially intended prevention of lymphocyte-mediat ed rejection.