Ruxolitinib In GvHD

The pathophysiological hallmark of GvHD after allo-HCT is an allogeneic donor T cell re-sponse against recipient antigens. This process is aggravated by increased processing and presentation of host antigens by donor APCs following conditioning treatment. The al-logeneic T cell response leads to inflammation, tissue damage and fibrosis and is mediated by extensive production of inflammatory cytokines such as IL-1, IL-2R, IL-6 and TNF. The signal transmission of inflammatory cytokines in effector cells requires activation of specialized kinases from the family of the Janus kinases. These kinases, JAK1, 2 and 3 are linked to cytokine receptors, and are activated upon binding of the cytokine to the receptor of the inflammatory effector. The JAK1/2 kinase inhibitor Ruxolitinib (INC424) is approved for myelofibrosis. In advanced myelofibrosis, Ruxolitinib lead to sustained clinical remissions with regard to constitutional symptoms, weight loss and spleen size in the majority of treated patients. Of note, clinical responses correlated with a marked reduction in inflammatory plasma cytokines. Importantly, cytokines down-regulated by Ruxolitinib in patients with myelofibrosis correspond to inflammatory effectors that mediate tissue damage and inflammation in GvHD. These are mainly the cytokines IL- 1, IL -6, TNF and IFN-gamma. Since Ruxolitinib suppresses the JAK1 / 2 cytokine response, we hypothesized that Ruxolitinib might attenuate the cytokine mediated inflammatory tissue damage in GVHD and thus might favourably affect the severity and course of GvHD after allo-HCT. In vitro, we demonstrated in an allogeneic system (major mismatch mixed-lymphocyte reactions) that co-incubation with Ruxolitinib strongly suppressed both the proliferation of alloge-neic T cells and the production of inflammatory cytokines. Using a very aggressive major mismatch mouse model of acute GvHD Ruxolitinib treatment signifi-cantly prolonged survival of animals (see Figure 1A). In addition, in these animals showed a reduced weight loss, significantly reduced histopathological GvHD severity, suppression of inflammatory cytokines in the serum and a reduction of donor T cells in GvHD target organs such as the intestines. Sole suppression of cytokine production or cytokine receptor activity by Ruxolitinib would be very similar to already established drugs for GvHD and no major conceptual advance. However we observed that Ruxolitinib did not only suppress cytokine production but also led to increased frequencies of FoxP3+ regulatory T cells. This cell type was previ-ously shown to lead to long-lasting tolerance as compared to the short-term immunosuppression achieved by conventional medication for GvHD.