633 - Human Mesenchymal Stem Cells Primed By Interferon-γ Ameliorate Gvhd in NOD/Sicd Mice through Indoleamine 2,3-Dioxygenase Activity

Abstract

Mesenchymal stem cells (MSCs) are drawing attention as a therapeutic challenge for immune-related diseases due to their immunosuppressive properties. In this study, we aimed to identify the impact of interferon (IFN) γ priming on immunomodulation by MSCs and to elucidate the possible mechanism underlying their unique properties applicable for the treatment of allogeneic conflicts. Infusion of MSCs primed with IFN-γ significantly reduced the symptoms of graft-versus-host disease (GVHD) in NOD/SCID mice, which resulted in an increase in the survival rate in comparison with naive MSC-infused mice. Infusion of IFN-γ-primed MSCs in which indoleamine 2,3-dioxygenase (IDO) was down-regulated did not elicit this effect. The IDO gene was expressed in MSCs via the IFN-γ/Janus kinase (JAK)/signal transducer and activator of transcription 1 (STAT1) pathway, and infusion of IDO-overexpressing MSCs increased the survival rate of GVHD mice in a manner similar to what was observed with IFN-γ-primed MSCs. In addition, IDO expression was commonly induced when MSCs were stimulated with IFN-γ, while it was marginal when they were treated with poly I:C that stimulates Toll-like receptor 3 or tumor necrosis factor-α. These data indicate that IFN-γ produced by activated T-cells leads to the induction of IDO expression in MSCs through the IFN-γ/JAK/STAT1 pathway, which results in suppression of T-cell proliferation. Our findings also suggest that cell therapy using MSCs primed with IFN-γ could be highly effective in treating allogeneic conflicts including GVHD.