Leukocyte integrin Mac-1 promotes acute cardiac allograft rejection

Abstract

BACKGROUND - In allograft rejection, recipient leukocytes and alloantibodies first target donor endothelial cells. Although the leukocyte integrin Mac-1 (αMβ2, CD11b/CD18) facilitates cell-cell interactions among leukocytes and interactions between leukocytes and endothelial cells or platelets, its role in allograft survival and vasculopathy is incompletely defined. METHODS AND RESULTS - This study examined parenchymal rejection and graft arterial disease after total allomismatched cardiac transplantation (BALB/c donor heart and B6 recipients) in wild-type (WT) and Mac-1-deficient (Mac-1) recipients. Recipient Mac-1 deficiency attenuated parenchymal rejection and significantly prolonged cardiac allograft survival from 8.3±1.3 days in WT recipient allografts (n=18) to 13.8±2.3 days in Mac-1 recipient allografts (n=6; P<0.0001). Accumulation of neutrophils and macrophages significantly decreased in Mac-1 compared with WT recipients. Adoptive transfer of WT but not Mac-1 macrophages to Mac-1 recipients exacerbated parenchymal rejection and reduced allograft survival; in contrast, adoptive transfer of WT neutrophils did not affect graft survival. Mac-1 macrophages expressed significantly lower levels of costimulatory molecules both in vivo and in vitro, and mixed lymphocyte reaction using alloantigen-primed Mac-1 macrophages resulted in significantly lower antigen-presenting function than for WT macrophages. Tumor necrosis factor-α production also fell in cultures with Mac-1 macrophages. Despite attenuation of acute rejection, recipient Mac-1-deficiency did not prevent late graft arterial disease. CONCLUSIONS - These studies demonstrate critical participation of Mac-1 in alloresponses during cellular allograft rejection. These observations establish a molecular target for modulating recipient responses to prolong graft survival. © 2008 American Heart Association, Inc.