TY - JOUR
T1 - Rapid ex vivo expansion of highly enriched human invariant natural killer T cells via single antigenic stimulation for cell therapy to prevent graft-versus-host disease
AU - TRUJILLO-OCAMPO, A. B.E.L.
AU - CHO, HYUN Y.U.N.W.O.O.
AU - HERRMANN, AMANDA C.
AU - RUIZ-VAZQUEZ, WILFREDO
AU - THORNTON, ANDREW B.
AU - HE, H. O.N.G.
AU - LI, D. A.N.
AU - QAZILBASH, MARIAM A.
AU - MA, Q. I.N.G.
AU - PORCELLI, STEVEN A.
AU - SHPALL, ELIZABETH J.
AU - MOLLDREM, JEFFREY
AU - IM, JIN S.
N1 - Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/8
Y1 - 2018/8
N2 - 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.
AB - 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.
KW - cell therapy
KW - ex vivo expansion
KW - graft-versus-host disease
KW - human iNK T cells
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U2 - 10.1016/j.jcyt.2018.05.007
DO - 10.1016/j.jcyt.2018.05.007
M3 - Article
C2 - 30076070
AN - SCOPUS:85050661898
SN - 1465-3249
VL - 20
SP - 1089
EP - 1101
JO - Cytotherapy
JF - Cytotherapy
IS - 8
ER -