Date: Monday, June 13, 2016
Session Name: Concurrent Session: Xenotransplantation: Animal Models
Session Time: 4:30pm-6:00pm
Presentation Time: 5:30pm-5:42pm
Location: Room 102
Xenotransplantation is a potential solution for the shortage of organs for transplantation. However, potent xenograft rejection responses present a formidable barrier. Mixed xenogeneic hematopoietic chimerism has been shown in mouse models to induce tolerance among T, B and NK cells. NK cells play an important role in the rejection of xenogeneic tissues. We have shown previously in an allogeneic mixed chimerism model that specific NK cell tolerance is induced. In a rat-to-mouse transplantation model, in contrast, induction of mixed xenogeneic chimerism led to global hyporesponsiveness of recipient NK cells. In this study, we investigated whether pig/human mixed chimerism could tolerize human NK cells in a humanized mouse model.
Pig/human mixed chimeric mice were generated by injection of pig bone marrow cells to irradiated pig cytokine transgenic NSG mice followed by injection of human fetal liver-derived CD34+ cells 3-7 days later. Control non-chimeric mice were injected with human CD34+ cells only. Human NK cell reconstitution was induced by hydrodynamic injection of plasmids encoding human Flt3L followed by injection of human IL-15/IL15 Fc–receptor alpha complex.
Our results showed that induction of human NK cells in pig/human mixed chimeras did not promote loss of pig chimerism. NK cells from pig/human mixed chimeric mice showed either specifically decreased cytotoxicity to pig cells or global hyporesponsiveness as determined by in vitro cytotoxicity assay, indicating that mixed xenogeneic chimerism resulted in variable and partial tolerance of human NK cells to pig cells. Bone marrow NK cells from chimeric mice showed decreased cytokine responses to K562 cell stimulation in vitro than NK cells from non-chimeric mice. Mixed xenogeneic chimerism did not hamper the maturation of human NK cells, but was associated with an alteration in NK cell subset distribution in the bone marrow. In summary, our results demonstrate that mixed xenogeneic chimerism is able to induce partial human NK cell tolerance to pig cells and support the use of this approach to inducing xenogeneic tolerance in the clinical setting. However, additional approaches are required to improve the efficacy of NK cell tolerance induction.
CITATION INFORMATION: Li H, Vishwasrao P, Holzl M, Chen S, Choi G, Zhao G, Sykes M. Impact of Mixed Xenogeneic Porcine Hematopoietic Chimerism on Human NK Cell Recognition in a Humanized Mouse Model. Am J Transplant. 2016;16 (suppl 3).
To cite this abstract in AMA style:Li H, Vishwasrao P, Holzl M, Chen S, Choi G, Zhao G, Sykes M. Impact of Mixed Xenogeneic Porcine Hematopoietic Chimerism on Human NK Cell Recognition in a Humanized Mouse Model. [abstract]. Am J Transplant. 2016; 16 (suppl 3). http://atcmeetingabstracts.com/abstract/impact-of-mixed-xenogeneic-porcine-hematopoietic-chimerism-on-human-nk-cell-recognition-in-a-humanized-mouse-model/. Accessed September 21, 2017.
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