title: MHC-matched induced pluripotent stem cells can attenuate cellular and humoral immune responses but are still susceptible to innate immunity in pigs.
abstract: Recent studies have revealed negligible immunogenicity of induced pluripotent stem (iPS) cells in syngeneic mice and in autologous monkeys. Therefore, human iPS cells would not elicit immune responses in the autologous setting. However, given that human leukocyte antigen (HLA)-matched allogeneic iPS cells would likely be used for medical applications, a more faithful model system is needed to reflect HLA-matched allogeneic settings. Here we examined whether iPS cells induce immune responses in the swine leukocyte antigen (SLA)-matched setting. iPS cells were generated from the SLA-defined C1 strain of Clawn miniature swine, which were confirmed to develop teratomas in mice, and transplanted into the testes (n = 4) and ovary (n = 1) of C1 pigs. No teratomas were found in pigs on 47 to 125 days after transplantation. A Mixed lymphocyte reaction revealed that T-cell responses to the transplanted MHC-matched (C1) iPS cells were significantly lower compared to allogeneic cells. The humoral immune responses were also attenuated in the C1-to-C1 setting. More importantly, even MHC-matched iPS cells were susceptible to innate immunity, NK cells and serum complement. iPS cells lacked the expression of SLA class I and sialic acids. The in vitro cytotoxic assay showed that C1 iPS cells were targeted by NK cells and serum complement of C1. In vivo, the C1 iPS cells developed larger teratomas in NK-deficient NOG (T-B-NK-) mice (n = 10) than in NK-competent NOD/SCID (T-B-NK+) mice (n = 8) (p<0.01). In addition, C1 iPS cell failed to form teratomas after incubation with the porcine complement-active serum. Taken together, MHC-matched iPS cells can attenuate cellular and humoral immune responses, but still susceptible to innate immunity in pigs.
authors.affiliation: Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Mizukami
authors.affiliation: Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan; Center for Development of Advanced Medical Technology, Jichi Medical University, Tochigi, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Abe
authors.affiliation: Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Ibaraki, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shibata
authors.affiliation: Center for Development of Advanced Medical Technology, Jichi Medical University, Tochigi, Japan.
authors.forename: Yukitoshi
authors.initials: Y
authors.lastname: Makimura
authors.affiliation: Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Shuh-hei
authors.initials: SH
authors.lastname: Fujishiro
authors.affiliation: Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Kimihide
authors.initials: K
authors.lastname: Yanase
authors.affiliation: Center for Development of Advanced Medical Technology, Jichi Medical University, Tochigi, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Hishikawa
authors.affiliation: Center for Development of Advanced Medical Technology, Jichi Medical University, Tochigi, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kobayashi
authors.affiliation: Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan; Center for Development of Advanced Medical Technology, Jichi Medical University, Tochigi, Japan; CREST, Japan Science and Technology Agency, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hanazono
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D056724:Immunity, Humoral; D007113:Immunity, Innate; D057026:Induced Pluripotent Stem Cells / Q000276:immunology / Q000637:transplantation*; D007694:Killer Cells, Natural / Q000276:immunology*; D008285:Major Histocompatibility Complex; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010053:Ovary / Q000276:immunology; D013552:Swine / Q000276:immunology*; D013556:Swine, Miniature / Q000276:immunology*; D013724:Teratoma / Q000209:etiology*; D013737:Testis / Q000276:immunology; D014182:Transplantation, Autologous
chemical_list: D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; C438668:swine leukocyte antigen