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Cytotherapy ; 20(8): 1089-1101, 2018 08.
Article in English | MEDLINE | ID: mdl-30076070

ABSTRACT

BACKGROUND AIMS: CD1d-restricted invariant natural killer (iNK) T cells are rare regulatory T cells that may contribute to the immune-regulation in allogeneic stem cell transplantation (ASCT). Here, we sought to develop an effective strategy to expand human iNK T cells for use in cell therapy to prevent graft-versus-host disease (GVHD) in ASCT. METHODS: Human iNK T cells were first enriched from peripheral blood mononuclear cells (PBMCs) using magnetic-activated cell sorting separation, then co-cultured with dendritic cells in the presence of agonist glycolipids, alpha-galactosylceramide, for 2 weeks. RESULTS: The single antigenic stimulation reliably expanded iNK T cells to an average of 2.8 × 107 per 5 × 108 PBMCs in an average purity of 98.8% in 2 weeks (N = 24). The expanded iNK T cells contained a significantly higher level of CD4+ and central memory phenotype (CD45RA-CD62L+) compared with freshly isolated iNK T cells, and maintained their ability to produce both Th-1 (interferon [IFN]γ and tumor necrosis factor [TNF]α) and Th-2 type cytokines (interleukin [IL]-4, IL-5 and IL-13) upon antigenic stimulation or stimulation with Phorbol 12-myristate 13-acetate/ionomycin. Interestingly, expanded iNK T cells were highly autoreactive and produced a Th-2 polarized cytokine production profile after being co-cultured with dendritic cells alone without exogenous agonist glycolipid antigen. Lastly, expanded iNK T cells suppressed conventional T-cell proliferation and ameliorated xenograft GVHD (hazard ratio, 0.1266; P < 0.0001). CONCLUSION: We have demonstrated a feasible approach for obtaining ex vivo expanded, highly enriched human iNK T cells for use in adoptive cell therapy to prevent GVHD in ASCT.


Subject(s)
Cell Culture Techniques/methods , Graft vs Host Disease/prevention & control , Immunotherapy, Adoptive , Lymphocyte Activation/physiology , Natural Killer T-Cells/cytology , Natural Killer T-Cells/physiology , Animals , Antigens, Differentiation, T-Lymphocyte/immunology , Cell Proliferation/physiology , Cell- and Tissue-Based Therapy/methods , Cells, Cultured , Feasibility Studies , Graft vs Host Disease/immunology , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Humans , Immunotherapy, Adoptive/methods , Mice , Mice, Inbred NOD , Mice, SCID , Mice, Transgenic , Natural Killer T-Cells/immunology , Transplantation, Heterologous , Transplantation, Homologous
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