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The BALB/c-specific polymorphic SIRPA enhances its affinity for human CD47, inhibiting phagocytosis against human cells to promote xenogeneic engraftment

Authors
  • Iwamoto, Chika
  • Takenaka, Katsuto
  • Urata, Shingo
  • Yamauchi, Takuji
  • Shima, Takahiro
  • Kuriyama, Takuro
  • Daitoku, Shinya
  • Saito, Yasuyuki
  • Miyamoto, Toshihiro
  • Iwasaki, Hiromi
  • Kitabayashi, Issay
  • Itoh, Katsuhiko
  • Kishimoto, Junji
  • Kohda, Daisuke
  • Matozaki, Takashi
  • Akashi, Koichi1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 12, 15, 16, 17
  • 1 Department of Medicine and Biosystemic Science
  • 2 Kyushu University Graduate School of Medical Sciences
  • 3 Laboratory of Biosignal Sciences
  • 4 Institute for Molecular and Cellular Regulation
  • 5 Gunma University
  • 6 Division of Hematological Malignancy
  • 7 National Cancer Center Research Institute
  • 8 Department of Clinical Molecular Biology
  • 9 Faculty of Medicine
  • 10 Kyoto University
  • 11 Digital Medicine Initiative
  • 12 Kyushu University
  • 13 Division of Structural Biology
  • 14 Medical Institute of Bioregulation
  • 15 Division of Molecular and Cellular Signaling
  • 16 Department of Biochemistry and Molecular Biology
  • 17 Kobe University Graduate School of Medicine
Type
Published Article
Journal
Experimental Hematology
Publisher
Elsevier
Publication Date
Jan 01, 2014
Accepted Date
Nov 07, 2013
Volume
42
Issue
3
Pages
163–171
Identifiers
DOI: 10.1016/j.exphem.2013.11.005
Source
Elsevier
License
Unknown

Abstract

It has been shown that in xenotransplantation of human cells into immunodeficient mice, the mouse strain background is critical. For example, the nonobese diabetic (NOD) strain is most efficient, the BALB/c is moderate, and the C57BL/6 is inefficient for human cell engraftment. We have shown that the NOD-specific polymorphism of the signal regulatory protein-alpha (Sirpa) allows NOD SIRPA to bind human CD47, and the resultant “don't eat me” signaling by this binding prevents host macrophages to engulf human grafts, thereby inhibiting rejection. Here we tested whether the efficient xenotransplantation capability of the BALB/c strain is also mediated by the SIRPA-CD47 self-recognition system. BALB/c SIRPA was capable of binding to human CD47 at an intermediate level between those of C57BL/6 SIRPA and NOD SIRPA. Consistent with its binding activity, BALB/c-derived macrophages exhibited a moderate inhibitory effect on human long-term culture-initiating cells in in vitro cultures, and showed moderate phagocytic activity against human hematopoietic stem cells. The increased affinity of BALB/c SIRPA for human CD47 was mounted at least through the BALB/c-specific L29V SNP within the IgV domain. Thus, the mouse strain effect on xenogeneic engraftment might be ascribed mainly to the binding affinity of strain-specific polymorphic SIRPA with human CD47. This information should be useful for developing a novel immunodeficient strain with superior efficiency for xenogeneic transplantation of human cells.

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