title: Added effects of dexamethasone and mesenchymal stem cells on early Natural Killer cell activation.
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.
authors.affiliation: Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Clive M
authors.initials: CM
authors.lastname: Michelo
authors.affiliation: Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Fasse
authors.affiliation: Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Bram
authors.initials: B
authors.lastname: van Cranenbroek
authors.affiliation: Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Katrin
authors.initials: K
authors.lastname: Linda
authors.affiliation: Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Arnold
authors.initials: A
authors.lastname: van der Meer
authors.affiliation: Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Heba
authors.initials: H
authors.lastname: Abdelrazik
authors.affiliation: Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud university medical center, Nijmegen, The Netherlands. Electronic address: irma.joosten@radboudumc.nl.
authors.forename: Irma
authors.initials: I
authors.lastname: Joosten
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D003907:Dexamethasone / Q000494:pharmacology* / Q000627:therapeutic use; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D006086:Graft vs Host Disease / Q000276:immunology* / Q000517:prevention & control; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type / Q000378:metabolism; D008213:Lymphocyte Activation; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D054353:Perforin / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D050797:STAT4 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D014180:Transplantation; D015854:Up-Regulation / Q000187:drug effects; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D003907:Dexamethasone; D007166:Immunosuppressive Agents; D007371:Interferon-gamma; D018664:Interleukin-12; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D037181:Lectins, C-Type; D054353:Perforin; D050797:STAT4 Transcription Factor; D050799:STAT5 Transcription Factor; D000099192:CD69 Antigens
keywords: NK cells; corticosteroids; hematopoietic stem cell transplantation; immunosuppressive drugs; mesenchymal stem cells