Selective ROCK2 inhibitor reverses experimental chronic graft-versus-host disease via concurrent regulation of STAT3/STAT5 phosphorylation (TRAN1P.933)

Abstract

Abstract Rho-associated kinase 2 (ROCK2) was recently shown to be implicated in regulation of IL-21 and IL-17 secretion in mice and humans. Here, we report that the potent and highly selective ROCK2 inhibitor KD025 effectively reverses an established chronic graft-versus-host (cGVHD) murine model driven by IL-21 and characterized by an aggressive multiorgan system fibrotic disease. KD025 treatment leads to a dose dependent decrease in the development of pathogenic pulmonary function which correlates with a marked reduction of antibody and collagen deposition in the lungs of treated mice to levels comparable to non-cGVHD controls. The spleens of mice treated with KD025 had a decrease in the frequency of germinal centers associated with a reduction in STAT3 and concurrent increase in STAT5 phosphorylation, supporting the molecular mechanism of targeted ROCK2 inhibition in humans. The critical role of STAT3 activation in this cGVHD model was further confirmed by data showing that mice transplanted with inducible STAT3 deficient T cells or BM cells had pulmonary function comparable to the healthy negative controls. Finally, KD025 effectively blocked the progression of sclerodermatous cGVHD model characterized by improvements in weight loss, posture and skin integrity of treated animals. Together, these data demonstrate the importance of ROCK2 signaling in STAT3-dependent regulation of cytokine secretion and highlight the potential of targeted ROCK2 inhibition for cGVHD therapy.