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Elucidation of mechanisms for macrophage-mediated xenograft refection and a novel approach to prevent macrophage-mediated xenograft rejection by gene introduction of human CD47 to xenogenic cells

阐明巨噬细胞介导的异种移植排斥的机制以及通过将人 CD47 基因引入异种细胞来预防巨噬细胞介导的异种移植排斥的新方法

基本信息

批准号：
16591257
负责人：
OHDAN Hideki
金额：
$ 2.3万
依托单位：
HIROSHIMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591257/
关键词：
Xenotransplatation Macrophage Rejection CD47 Transgenics

项目摘要

Xenotransplantation of pig organs to humans is a possible solution for the shortage of donor organs for transplantation. Although host macrophages are known to contribute at least in part to rapid clearance of transplanted xenogeneic cells, the mechanisms underlying macrophage-induced killing of xenogeneic cells has not been fully addressed. We here demonstrated that human reticulo-endothelial macrophages can phagocytose porcine cells in the absence of antibody or complement opsonization, and that the removal of α1,3-galactosyl xenoantigens from the porcine cells failed to prevent the phagocytosis. We also demonstrated that the interspecies incompatibility of CD47 significantly contributes to the phagocytosis of xenogeneic cells by macrophages. To further determine whether the expression of human CD47 on porcine cells could confer protection from phagocytosis by human macrophages, we generated human CD47-expressing porcine cell lines by transfecting the porcine B lymphoma-like cells with a human CD47 expressing plasmid. Human CD47 expression on porcine cells radically reduced the susceptibility of the cells to phagocytosis by human reticulo-endothelial macrophages, regardless of the presence or absence of antibody opsonization. These results indicate that the interspecies incompatibility of CD47 significantly contributes to the rejection of xenogeneic cells by macrophages. Genetic manipulation of porcine cells for expression of human CD47 may provide a novel approach in preventing macrophage-mediated xenograft rejection through inhibitory CD47-SIRPα signaling.

猪器官异种移植是解决移植供体短缺的一种可能途径。尽管已知宿主巨噬细胞至少部分有助于移植的异种细胞的快速清除，但巨噬细胞诱导的异种细胞杀伤的潜在机制尚未完全解决。我们在此证明，人网状内皮巨噬细胞在没有抗体或补体调理作用的情况下可以吞噬猪细胞，并且从猪细胞中去除α 1，3-半乳糖基异种抗原未能阻止吞噬作用。我们还证明了CD 47的种间不相容性显著有助于巨噬细胞吞噬异种细胞。为了进一步确定人CD 47在猪细胞上的表达是否可以提供保护以免受人巨噬细胞的吞噬作用，我们通过用人CD 47表达质粒转染猪B淋巴瘤样细胞来产生表达人CD 47的猪细胞系。人CD 47在猪细胞上的表达从根本上降低了细胞对人网状内皮巨噬细胞吞噬作用的敏感性，无论是否存在抗体调理作用。这些结果表明，种间不相容性的CD 47显着有助于异种细胞的排斥巨噬细胞。猪细胞表达人CD 47的基因操作可能为通过抑制CD 47-SIRPα信号通路预防巨噬细胞介导的异种移植排斥提供一种新的方法。