Role for CD47-SIRPα signaling in xenograft rejection by macrophages

Proceedings of the National Academy of Sciences of the United States of America - Tập 104 Số 12 - Trang 5062-5066 - 2007
Kentaro Ide1, Hui Wang2, Hiroyuki Tahara1, Jianxiang Liu3, Xiaoying Wang3, Toshimasa Asahara1, Megan Sykes2, Yong‐Guang Yang2, Hideki Ohdan1
1*Department of Surgery, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Science, Hiroshima University, Hiroshima 734-8551, Japan;
2Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, United States,
3Neuroprotection Research Laboratory, Department of Radiology and Neurology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, MA 02129, United States.

Tóm tắt

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)α is a critical immune inhibitory receptor on macrophages, and its interaction with CD47, a ligand for SIRPα, 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 SIRPα 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 SIRPα on human macrophages, providing a novel approach to preventing macrophage-mediated xenograft rejection.

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Proceedings of the National Academy of Sciences of the United States of America

Tập 104 Số 12

5062-5066

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