Wang Hui, VerHalen Jon, Madariaga Maria Lucia, Xiang Shuanglin, Wang Shumei, Lan Ping, Oldenborg Per-Arne, Sykes Megan, Yang Yong-Guang
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.
Blood. 2007 Jan 15;109(2):836-42. doi: 10.1182/blood-2006-04-019794. Epub 2006 Sep 28.
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.
信号调节蛋白α（SIRPα）是巨噬细胞上一种关键的免疫抑制受体，它与SIRPα的配体CD47相互作用可防止自身吞噬作用。我们推测CD47的种间不相容性可能导致巨噬细胞对异种细胞的排斥。在此，我们表明猪的CD47不与小鼠的SIPRα相互作用。与CD47基因敲除小鼠细胞类似，猪红细胞（RBC）未能在小鼠巨噬细胞中诱导SIRPα酪氨酸磷酸化。用抗小鼠SIRPα单克隆抗体（P84）阻断SIRPα可显著增强对CD47+/+小鼠细胞的吞噬作用，但不影响小鼠巨噬细胞对猪细胞或CD47基因敲除小鼠细胞的吞噬。巨噬细胞不吞噬CD47基因敲除小鼠细胞的CD47缺陷小鼠，与野生型小鼠受体相比，对猪红细胞的清除明显延迟。此外，猪细胞上小鼠CD47的表达在体外和体内均显著降低了小鼠巨噬细胞对其的吞噬作用。这些结果表明，CD47的种间不相容性对巨噬细胞吞噬异种细胞有显著影响，并提示对供体CD47进行基因操作以改善其与受体SIRPα的相互作用可能提供一种预防吞噬细胞介导的异种移植排斥的新方法。
