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Impact of Mixed Xenogeneic Porcine Hematopoietic Chimerism on Human NK Cell Recognition in a Humanized Mouse Model

Li, H. W., Vishwasrao, P., Holzl, M. A., Chen, S., Choi, G., Zhao, G. & Sykes, E. M., Feb-2017, In : American Journal of Transplantation. 17, 2, p. 353-364 12 p.

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  • Impact of Mixed Xenogeneic Porcine Hematopoietic Chimerism

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  • H. W. Li
  • Paresh Vishwasrao
  • M. A. Holzl
  • S. Chen
  • G. Choi
  • G. Zhao
  • Edward M. Sykes

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-gamma) 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.

Original languageEnglish
Pages (from-to)353-364
Number of pages12
JournalAmerican Journal of Transplantation
Volume17
Issue number2
Publication statusPublished - Feb-2017

    Keywords

  • NATURAL-KILLER-CELLS, CLASS-I GENES, T-CELL, SURFACE EXPRESSION, ENDOTHELIAL-CELLS, TOLERANCE, XENOTRANSPLANTATION, CYTOTOXICITY, INDUCTION, RECEPTORS

ID: 46001752