Role for CD47-SIRPα signaling in xenograft rejection by macrophages
Role for CD47-SIRPα signaling in xenograft rejection by macrophages
复制标题
DOI：
10.1073/pnas.0609661104
复制
发表时间：
2007-03-20
影响因子：
11.1
通讯作者：
Ohdan, Hideki
中科院分区：
文献类型：
--
作者：
Ide, Kentaro;Wang, Hui;Ohdan, Hideki
我们以前已经证明，即使在没有Ab或补体调理作用的情况下，人巨噬细胞也可以吞噬猪细胞，这表明巨噬细胞是异种移植的关键免疫障碍。最近的报告表明，信号调节蛋白（SIRP）α是巨噬细胞上的关键免疫抑制受体，其与CD47（SIRP α的配体）的相互作用可防止自体吞噬作用。考虑到猪和人CD 47之间氨基酸序列的有限相容性（73%），我们假设CD 47的种间不相容性可能有助于巨噬细胞对异种细胞的排斥。在本研究中，我们已经证明猪CD47不诱导人巨噬细胞样细胞系中的SIRPa酪氨酸磷酸化，并且可溶性人CD47-Fc融合蛋白抑制人巨噬细胞对猪细胞的吞噬活性。此外，我们已经证实，操纵猪细胞表达人CD47从根本上降低了细胞对人巨噬细胞吞噬作用的敏感性。这些结果表明，种间不相容性的CD47显着有助于异种细胞的排斥巨噬细胞。猪细胞上人CD47的遗传诱导可以提供对人巨噬细胞上SIRPa的抑制性信号传导，提供预防巨噬细胞介导的异种移植排斥的新方法。
We have previously proven that human macrophages can phagocytose porcine cells even in the absence of Ab or complement opsonization, indicating that macrophages present a pivotal immunological obstacle to xenotransplantation. A recent report indicates that the signal regulatory protein (SIRP)alpha is a critical immune inhibitory receptor on macrophages, and its interaction with CD47, a ligand for SIRP alpha, prevents autologous phagocytosis. Considering the limited compatibility (73%) in amino acid sequences between pig and human CD47, we hypothesized that the interspecies incompatibility of CD47 may contribute to the rejection of xenogeneic cells by macrophages. In the present study, we have demonstrated that porcine CD47 does not induce SIRPa tyrosine phosphorylation in human macrophage-like cell line, and soluble human CD47-Fc fusion protein inhibits the phagocytic activity of human macrophages toward porcine cells. In addition, we have verified that manipulation of porcine cells for expression of human CD47 radically reduces the susceptibility of the cells to phagocytosis by human macrophages. These results indicate that the interspecies incompatibility of CD47 significantly contributes to the rejection of xenogeneic cells by macrophages. Genetic induction of human CD47 on porcine cells could provide inhibitory signaling to SIRPa on human macrophages, providing a novel approach to preventing macrophage-mediated xenograft rejection.