title: Impact of Mixed Xenogeneic Porcine Hematopoietic Chimerism on Human NK Cell Recognition in a Humanized Mouse Model.
abstract: Mixed chimerism is a promising approach to inducing allograft and xenograft tolerance. Mixed allogeneic and xenogeneic chimerism in mouse models induced specific tolerance and global hyporesponsiveness, respectively, of host mouse natural killer (NK) cells. In this study, we investigated whether pig/human mixed chimerism could tolerize human NK cells in a humanized mouse model. Our results showed no impact of induced human NK cell reconstitution on porcine chimerism. NK cells from most pig/human mixed chimeric mice showed either specifically decreased cytotoxicity to pig cells or global hyporesponsiveness in an in vitro cytotoxicity assay. Mixed xenogeneic chimerism did not hamper the maturation of human NK cells but was associated with an alteration in NK cell subset distribution and interferon gamma (IFN-γ) production in the bone marrow. In summary, we demonstrate that mixed xenogeneic chimerism induces human NK cell hyporesponsiveness to pig cells. Our results support the use of this approach to inducing xenogeneic tolerance in the clinical setting. However, additional approaches are required to improve the efficacy of tolerance induction while ensuring adequate NK cell functions.
authors.affiliation: Columbia Center for Translational Immunology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.
authors.forename: H W
authors.initials: HW
authors.lastname: Li
authors.affiliation: Columbia Center for Translational Immunology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.|Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Vishwasrao
authors.affiliation: Columbia Center for Translational Immunology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.
authors.forename: M A
authors.initials: MA
authors.lastname: Hölzl
authors.affiliation: Columbia Center for Translational Immunology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.
authors.forename: S
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.|Department of Hematology, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Choi
authors.affiliation: Columbia Center for Translational Immunology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.
authors.forename: G
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Columbia Center for Translational Immunology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.
authors.forename: M
authors.initials: M
authors.lastname: Sykes
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D013552:Swine; D013556:Swine, Miniature; D018183:Transplantation Chimera / Q000276:immunology*; D019172:Transplantation Conditioning; D014183:Transplantation, Heterologous
keywords: animal models: murine; basic (laboratory) research/science; bone marrow/hematopoietic stem cell transplantation; immunobiology; natural killer (NK) cells/NK receptors; tolerance: chimerism; translational research/science; xenoantigen; xenotransplantation