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 Blood, 15 January 2007, Vol. 109, No. 2, pp. 836-842.
Prepublished online as a Blood First Edition Paper on September 28, 2006; DOI 10.1182/blood-2006-04-019794.

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TRANSPLANTATION

Attenuation of phagocytosis of xenogeneic cells by manipulating CD47

Hui Wang1,2, Jon VerHalen1, Maria Lucia Madariaga1, Shuanglin Xiang3, Shumei Wang1, Ping Lan1, Per-Arne Oldenborg4, Megan Sykes1, and Yong-Guang Yang1,2,

1 Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA; 2 Wenzhou Medical College, Wenzhou, China; 3 Beth Israel Deaconess Medical Center of Harvard Medical School, Boston, MA; 4 Department of Integrative Medical Biology, Section for Histology and Cell Biology, Umeå University, Umeå, Sweden

Signal regulatory protein {alpha} (SIRP{alpha}) is a critical immune inhibitory receptor on macrophages, and its interaction with CD47, a ligand for SIRP{alpha}, prevents autologous phagocytosis. We hypothesized that interspecies incompatibility of CD47 may contribute to the rejection of xenogeneic cells by macrophages. Here, we show that pig CD47 does not interact with mouse SIPR{alpha}. Similar to CD47–/– mouse cells, porcine red blood cells (RBCs) failed to induce SIRP{alpha} tyrosine phosphorylation in mouse macrophages. Blocking SIRP{alpha} with antimouse SIRP{alpha} mAb (P84) significantly enhanced the phagocytosis of CD47+/+ mouse cells, but did not affect the engulfment of porcine or CD47–/– mouse cells by mouse macrophages. CD47-deficient mice, whose macrophages do not phagocytose CD47–/– mouse cells, showed markedly delayed clearance of porcine RBCs compared with wild-type mouse recipients. Furthermore, mouse CD47 expression on porcine cells markedly reduced their phagocytosis by mouse macrophages both in vitro and in vivo. These results indicate that interspecies incompatibility of CD47 contributes significantly to phagocytosis of xenogeneic cells by macrophages and suggest that genetic manipulation of donor CD47 to improve its interaction with the recipient SIRP{alpha} may provide a novel approach to prevent phagocyte-mediated xenograft rejection.


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