Submitted April 26, 2006
Accepted August 12, 2006
Attenuation of phagocytosis of xenogeneic cells by
manipulating CD47
Hui Wang, Jon VerHalen, Maria Lucia Madariaga, Shuanglin Xiang, Shumei Wang, Ping Lan, Per-Arne Oldenborg, Megan Sykes, and Yong-Guang Yang*
Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Beth Israel Deaconess Medical Center of Harvard Medical School, Boston, MA
Section for Histology and Cell Biology, Umea University, Umea, Sweden
* Corresponding author; email: yongguang.yang{at}tbrc.mgh.harvard.edu.
Signal regulatory protein (SIRP)
is a critical
immune inhibitory receptor on macrophages, and its
interaction with CD47, a ligand for SIRP, 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. Similar
to CD47-/- mouse cells, porcine RBCs failed to induce
SIRP tyrosine phosphorylation in mouse
macrophages. Blocking SIRP with anti- mouse
SIRP 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 to 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 may provide a novel
approach to prevent phagocyte-mediated xenograft rejection.
