title: The BALB/c-specific polymorphic SIRPA enhances its affinity for human CD47, inhibiting phagocytosis against human cells to promote xenogeneic engraftment.
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.
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Chika
authors.initials: C
authors.lastname: Iwamoto
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Katsuto
authors.initials: K
authors.lastname: Takenaka
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Urata
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Yamauchi
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shima
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Kuriyama
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Daitoku
authors.affiliation: Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Miyamoto
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Iwasaki
authors.affiliation: Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Issay
authors.initials: I
authors.lastname: Kitabayashi
authors.affiliation: Department of Clinical Molecular Biology, Faculty of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Itoh
authors.affiliation: Digital Medicine Initiative, Kyushu University, Fukuoka, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Kishimoto
authors.affiliation: Division of Structural Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kohda
authors.affiliation: Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan; Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matozaki
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. Electronic address: akashi@med.kyushu-u.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive / Q000276:immunology; D051928:CD47 Antigen / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D006085:Graft Survival / Q000276:immunology; D006367:HeLa Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D010587:Phagocytosis / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D014183:Transplantation, Heterologous
chemical_list: D051928:CD47 Antigen; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic