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

Research output: Contribution to journalArticle

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)
JournalCytotherapy
DOIs
StateAccepted/In press - Jan 1 2018

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Natural Killer T-Cells
Graft vs Host Disease
Cell- and Tissue-Based Therapy
Stem Cell Transplantation
Glycolipids
Dendritic Cells
Blood Cells
Cytokines
Ionomycin
Interleukin-13
Cell Separation
Interleukin-5
Regulatory T-Lymphocytes
Heterografts
Interleukin-4
Interferons
Acetates
Tumor Necrosis Factor-alpha
Cell Proliferation
T-Lymphocytes

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
  • Transplantation
  • Cancer Research

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., ... IM, JIN. S. (Accepted/In press). 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. https://doi.org/10.1016/j.jcyt.2018.05.007

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. / 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.

In: Cytotherapy, 01.01.2018.

Research output: Contribution to journalArticle

TRUJILLO-OCAMPO, ABEL, CHO, HYUNYUNWOO, HERRMANN, AMANDAC, RUIZ-VAZQUEZ, WILFREDO, THORNTON, ANDREWB, HE, HONG, LI, DAN, QAZILBASH, MARIAMA, MA, QING, Porcelli, SA, SHPALL, ELIZABETHJ, MOLLDREM, JEFFREY & IM, JINS 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. https://doi.org/10.1016/j.jcyt.2018.05.007
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. / 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. In: Cytotherapy. 2018.
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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 (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.",
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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.

PY - 2018/1/1

Y1 - 2018/1/1

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.

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KW - graft-versus-host disease

KW - human iNK T cells

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