Attenuation of phagocytosis of xenogeneic cells by manipulating CD47
Attenuation of phagocytosis of xenogeneic cells by manipulating CD47
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DOI：
10.1182/blood-2006-04-019794
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发表时间：
2007-01-15
期刊：
影响因子：
20.3
通讯作者：
Yang, Yong-Guang
中科院分区：
文献类型：
--
作者：
Wang, Hui;VerHalen, Jon;Yang, Yong-Guang
信号调节蛋白α(SIRPα)是巨噬细胞上一种重要的免疫抑制受体，它与SIRPα的配体CD47相互作用可阻止自体吞噬。我们推测CD47的种间不相容可能参与了巨噬细胞对异种细胞的排斥反应。在这里，我们证明了猪CD47不与小鼠SIPRα相互作用。与CD47(-/-)小鼠细胞相似，猪红细胞(RBC)不能诱导小鼠巨噬细胞SIRPα酪氨酸磷酸化。用抗小鼠SIRPα单抗(P84)阻断SIRPα可显著增强CD47(+/+)小鼠细胞的吞噬功能，但不影响小鼠巨噬细胞吞噬猪或CD47(-/-)小鼠细胞的能力。CD47缺陷小鼠的巨噬细胞不吞噬CD47(-/-)小鼠细胞，与野生型小鼠受体相比，猪红细胞的清除明显延迟。此外，小鼠CD47在猪细胞上的表达显著降低了小鼠巨噬细胞在体外和体内的吞噬能力。这些结果表明，CD47的种间不相容显著促进了巨噬细胞对异种细胞的吞噬作用，提示对供者CD47进行基因操作以改善其与受体SIRPA的相互作用可能为预防吞噬细胞介导的异种移植排斥反应提供一种新的途径。(C)美国血液病学会2007年
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 SIRPa may provide a novel approach to prevent phagocyte-mediated xenograft rejection. (c) 2007 by The American Society of Hematology