Enhanced Immunosuppressive Properties of Human Mesenchymal Stem Cells Primed by Interferon-gamma

Mesenchymal stemcells (MSCs) are of particular interest for the treatment of immune- related diseases owing to their immunosuppressive properties. In this study, we aimed to identify the effect of interferon (IFN)-gamma priming on immunomodulation by MSCs and elucidate the possible mechanism underlying their properties for the clinical treatment of allogeneic conflicts. Infusion ofMSCs primed with IFN-gamma significantly reduced the symptoms of graft-versus-host disease (GVHD) inNOD-SCIDmice, thereby increasing survival ratewhen comparedwith naive MSC-infused mice. However, infusion of IFN-gamma-primed MSCs in which indoleamine 2,3-dioxygenase (IDO) was downregulated did not elicit this effect. The IDO gene was expressed in MSCs via the IFN-gamma-Janus kinase (JAK)signal transducer and activator of transcription 1 (STAT1) pathway, and the infusion of IDO-over-expressing MSCs increased survival rate in an in vivo GVHDmodel, similar to infusion of IFN-gamma-primed MSCs. These data indicate that IFN-gamma production by activated T-cells is correlated with the induction of IDO expression in MSCs via the IFN-gamma-JAK-STAT1 pathway, which in turn results in the suppression of T-cell proliferation. Our findings also suggest that cell therapy based on MSCs primed with IFN-gamma can be used for the clinical treatment of allogeneic conflicts, including GVHD. (c) 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license.