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(Circulation. 2008;117:1997-2008.)
© 2008 American Heart Association, Inc.

Transplantation

Leukocyte Integrin Mac-1 Promotes Acute Cardiac Allograft Rejection

Koichi Shimizu, MD, PhD; Peter Libby, MD; Rica Shubiki, BA; Masashi Sakuma, MD; Yunmei Wang, PhD; Kenichi Asano, MD, PhD; Richard N. Mitchell, MD, PhD^*; Daniel I. Simon, MD, PhD^*

From the Donald W. Reynolds Cardiovascular Clinical Research Center, Cardiovascular Division, Department of Medicine (K.S., P.L., R.S.) and Department of Pathology (K.A., R.N.M.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass, and Division of Cardiovascular Medicine, University Hospitals of Cleveland–Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio (M.S., Y.W., D.I.S.).

Correspondence to Koichi Shimizu, MD, PhD, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, 77 Ave Louis Pasteur, NRB7, Boston, MA 02115. E-mail ksmz{at}rics.bwh.harvard.edu

Received June 28, 2007; accepted February 13, 2008.

Background— In allograft rejection, recipient leukocytes and alloantibodies first target donor endothelial cells. Although the leukocyte integrin Mac-1 (_Mβ2, 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- 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.

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