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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.

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.

journal_name

Cytotherapy

journal_title

Cytotherapy

authors

Trujillo-Ocampo A,Cho HW,Herrmann AC,Ruiz-Vazquez W,Thornton AB,He H,Li D,Qazilbash MA,Ma Q,Porcelli SA,Shpall EJ,Molldrem J,Im JS

doi

10.1016/j.jcyt.2018.05.007

subject

Has Abstract

pub_date

2018-08-01 00:00:00

pages

1089-1101

issue

eissn

1465-3249

issn

1477-2566

pii

S1465-3249(18)30518-8

journal_volume

pub_type

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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.