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

A. B.E.L. TRUJILLO-OCAMPO, HYUN Y.U.N.W.O.O. CHO, AMANDA C. HERRMANN, WILFREDO RUIZ-VAZQUEZ, ANDREW B. THORNTON, H. O.N.G. HE, D. A.N. LI, MARIAM A. QAZILBASH, Q. I.N.G. MA, STEVEN A. PORCELLI, ELIZABETH J. SHPALL, JEFFREY MOLLDREM, JIN S. IM

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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 (CD45RACD62L+) 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.

Original languageEnglish (US)
Pages (from-to)1089-1101
Number of pages13
JournalCytotherapy
Volume20
Issue number8
DOIs
StatePublished - Aug 2018

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Keywords

  • cell therapy
  • ex vivo expansion
  • graft-versus-host disease
  • human iNK T cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Genetics(clinical)
  • Cell Biology
  • Cancer Research
  • Transplantation

Cite this

TRUJILLO-OCAMPO, A. B. E. L., CHO, HYUN. Y. U. N. W. O. O., HERRMANN, AMANDA. C., RUIZ-VAZQUEZ, WILFREDO., THORNTON, ANDREW. B., HE, H. O. N. G., LI, D. A. N., QAZILBASH, MARIAM. A., MA, Q. I. N. G., PORCELLI, STEVEN. A., SHPALL, ELIZABETH. J., MOLLDREM, JEFFREY., & IM, JIN. S. (2018). 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. Cytotherapy, 20(8), 1089-1101. https://doi.org/10.1016/j.jcyt.2018.05.007