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.
Highlights
Solid organ and hematopoietic stem cell transplantation (HSCT) are currently life saving treatments for many patients suffering from either benign or malignant disorders
natural killer (NK)-cells were stimulated with either 50ng/mL IL-12 (Gibco, Life technologies) or 100U/mL IL-2 (Chiron, Amsterdam, the Netherlands) and incubated at 37 °C, 95% humidity and 5% CO2 for 16h
Transplant recipients receive life-long administration of immunosuppressive drugs (ISD), but much is yet to be learned regarding the impact of these drugs on NK-cells [21], innate immune cells that recently gained interest for their allo-reactive and therapeutic potential [6]
Summary
Solid organ and hematopoietic stem cell transplantation (HSCT) are currently life saving treatments for many patients suffering from either benign or malignant disorders. Leading causes of transplantation-related mortality are graft rejection and Graft-versus-Host Disease (GvHD) [1,2,3]. These complications are due to an unwanted activity of the immune system. T-cells are the primary drivers of acute cellular rejection, recent studies have claimed natural killer (NK) cell allo-reactivity in influencing transplantation outcome [4,5,6]. There is increased interest in the influence of NK-cells on clinical outcomes following allogeneic transplantation [6]. A balance between activatory and inhibitory receptor signaling regulates the function of NK-cells.
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