Human Adipose-Derived Mesenchymal Stem Cells Modulate Experimental Autoimmune Arthritis by Modifying Early Adaptive T Cell Responses
AlphaMed Press 2015
STEM CELLS 2015;33:3493–3503 www.StemCells.com http://dx.doi.org/10.1002/stem.2113
MERCEDES LOPEZ-SANTALLA,a PABLO MANCHE~NO-CORVO,b RAMON MENTA,b JUAN LOPEZ-BELMONTE,c OLGA DELAROSA,b JUAN A. BUEREN,a WILFRIED DALEMANS,d ELEUTERIO LOMBARDO,b MARINA I. GARINa
Mesenchymal stem cells (MSCs) are multipotent stromal cells with immunosuppressive properties. They have emerged as a very promising treatment for autoimmunity and inflammatory diseases such as rheumatoid arthritis. Recent data have identified that GM-CSF-expressing CD4 T cells and Th17 cells have critical roles in the pathogenesis of arthritis and other inflammatory diseases. Although many studies have demonstrated that MSCs can either prevent or suppress inflammation, no studies have addressed their modulation on GM-CSF-expressing CD4 T cells and on the plasticity of Th17 cells. To address this, a single dose of human expanded adiposederived mesenchymal stem cells (eASCs) was administered to mice with established collageninduced arthritis. A beneficial effect was observed soon after the infusion of the eASCs as shown by a significant decrease in the severity of arthritis. This was accompanied by reduced number of pathogenic GM-CSF1CD41 T cells in the spleen and peripheral blood and by an increase in the number of different subsets of regulatory T cells like FOXP31CD41 T cells and IL101IL172CD41 T cells in the draining lymph nodes (LNs). Interestingly, increased numbers of Th17 cells coexpressing IL10 were also found in draining LNs. These results demonstrate that eASCs ameliorated arthritis after the onset of the disease by reducing the total number of pathogenic GM-CSF1CD41 T and by increasing the number of different subsets of regulatory T cells in draining LNs, including Th17 cells expressing IL10. All these cellular responses, ultimately, lead to the reestablishment of the regulatory/inflammatory balance in the draining LNs.
Altogether, our results identify, for the first time, a novel mechanism by which eASCs modulate ongoing immune responses by promoting an early adaptive regulatory T cell signature characterized by decreased levels of pathogenic GM-CSF-secreting T cells, increased levels of regulatory T cells and plasticity of effector Th17 cells toward an IL10-driven anti-inflammatory response thus restoring the regulatory/inflammatory balance following the onset of the disease.