Attenuation of phagocytosis of xenogeneic cells by manipulating CD47.
Signal regulatory protein alpha (SIRPalpha) is a critical immune inhibitory receptor on macrophages, and its interaction with CD47, a ligand for SIRPalpha, 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 SIPRalpha. Similar to CD47-/- mouse cells, porcine red blood cells (RBCs) failed to induce SIRPalpha tyrosine phosphorylation in mouse macrophages. Blocking SIRPalpha with antimouse SIRPalpha 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 SIRPalpha may provide a novel approach to prevent phagocyte-mediated xenograft rejection.
Wang
Hui
H
Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, MGH-East, Bldg 149-5102, 13th St, Boston, MA 02129, USA.
VerHalen
Jon
J
Madariaga
Maria Lucia
ML
Xiang
Shuanglin
S
Wang
Shumei
S
Lan
Ping
P
Oldenborg
Per-Arne
PA
Sykes
Megan
M
Yang
Yong-Guang
YG
D000818:Animals; D051928:CD47 Antigen / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006084:Graft Rejection / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis / Q000276:immunology; D011971:Receptors, Immunologic / Q000276:immunology; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors; D014183:Transplantation, Heterologous
D051928:CD47 Antigen; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic