Ruxolitinib, a JAK1/JAK2 selective inhibitor, ameliorates acute and chronic steroid-refractory GvHD mouse models

Abstract

Aim: Graft-versus-host disease (GvHD) is a major complication arising in patients undergoing allogenic hematopoietic stem cell transplantation. Material & methods: We tested ruxolitinib (a selective JAK1/2 inhibitor) efficacy in three different preclinical models of GvHD. Results: Ruxolitinib, at doses that mimic clinically achievable human JAK/signal transducers and activators of transcription target inhibition, significantly reduced alloreactive T-cell activation and infiltration in the lung and skin, leading to improved outcomes in two experimental models of steroid-refractory acute and chronic GvHD. Additionally, we describe a novel humanized GvHD model in which immunodeficient NOG animals are engineered to produce human IL-15 to facilitate enhanced T- and NK cell engraftment, leading to severe GvHD. Conclusion: Ruxolitinib treatment ameliorated disease symptoms resulting from targeted immune modulation via JAK/signal transducers and activators of transcription signaling inhibition.

Keywords: JAK; corticosteroid; cytokines; graft-versus-host disease; ruxolitinib; stem cell transplantation; steroid refractory.