Added effects of dexamethasone and mesenchymal stem cells on early Natural Killer cell activation

Transpl Immunol. 2016 Jul:37:1-9. doi: 10.1016/j.trim.2016.04.008. Epub 2016 Apr 30.

Abstract

Graft rejection and graft-versus-host disease are leading causes of transplant related mortality despite advancements in immunosuppressive therapy. Mesenchymal stem cells (MSCs) offer a promising addition to immunosuppressive drugs (ISD), while NK-cells are increasingly used as effector cells in graft-versus-leukemia. Combined therapy of ISD, NK-cells and/or MSCs is used in clinical practice. Here, we examined the effects of MSCs and selected ISD (tacrolimus, cyclosporin A, mycophenolic acid, dexamethasone) treatment on early NK-cell activation. We assessed STAT4 and STAT5 phosphorylation triggered by IL-12 and IL-2, respectively. Furthermore, we determined IFNγ, perforin production and the expression pattern of selected NK-cell receptors. Of all drugs tested, only dexamethasone inhibited NK-cell STAT4 and STAT5 phosphorylation. All ISD, with the exception of MPA, significantly inhibited IFNγ, and only dexamethasone inhibited upregulation of early activation markers CD69 and CD25 (IL-2 condition only). MSCs inhibited IL-2 induced NK cell STAT5 phosphorylation, IFNγ production and CD69 upregulation, and IL-12 induced IFNγ and perforin production. While MSCs mediated inhibition of CD69 expression was cell contact dependent, inhibition of IFNγ and perforin production, as well as STAT5 phosphorylation was cell-contact independent. Importantly, dexamethasone augmented MSCs mediated inhibition of both IL-12 and IL-2 induced CD69 expression and IFNγ production, as well as IL-2 induced STAT5 phosphorylation. Taken together, these novel insights may help the design of future NK-cell and MSCs based immunotherapy.

Keywords: NK cells; corticosteroids; hematopoietic stem cell transplantation; immunosuppressive drugs; mesenchymal stem cells.

MeSH terms

  • Antigens, CD / metabolism
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • Cells, Cultured
  • Combined Modality Therapy
  • Dexamethasone / pharmacology*
  • Dexamethasone / therapeutic use
  • Graft Rejection / immunology*
  • Graft Rejection / prevention & control
  • Graft vs Host Disease / immunology*
  • Graft vs Host Disease / prevention & control
  • Graft vs Leukemia Effect / immunology*
  • Humans
  • Immunosuppressive Agents / pharmacology*
  • Immunosuppressive Agents / therapeutic use
  • Interferon-gamma / metabolism
  • Interleukin-12 / immunology
  • Interleukin-2 / immunology
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Killer Cells, Natural / immunology*
  • Lectins, C-Type / metabolism
  • Lymphocyte Activation
  • Mesenchymal Stem Cells / immunology*
  • Perforin / metabolism
  • Phosphorylation / drug effects
  • STAT4 Transcription Factor / metabolism
  • STAT5 Transcription Factor / metabolism
  • Transplantation*
  • Up-Regulation / drug effects

Substances

  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD69 antigen
  • Immunosuppressive Agents
  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit
  • Lectins, C-Type
  • STAT4 Transcription Factor
  • STAT5 Transcription Factor
  • Perforin
  • Interleukin-12
  • Dexamethasone
  • Interferon-gamma