Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease

Blood. 2014 Jun 12;123(24):3832-42. doi: 10.1182/blood-2013-12-543736. Epub 2014 Apr 7.

Abstract

Graft-versus-host-disease (GVHD) is a severe complication of allogeneic hematopoietic cell transplantation (allo-HCT) characterized by the production of high levels of proinflammatory cytokines. Activated Janus kinases (JAKs) are required for T-effector cell responses in different inflammatory diseases, and their blockade could potently reduce acute GVHD. We observed that inhibition of JAK1/2 signaling resulted in reduced proliferation of effector T cells and suppression of proinflammatory cytokine production in response to alloantigen in mice. In vivo JAK 1/2 inhibition improved survival of mice developing acute GVHD and reduced histopathological GVHD grading, serum levels of proinflammatory cytokines, and expansion of alloreactive luc-transgenic T cells. Mechanistically, we could show that ruxolitinib impaired differentiation of CD4(+) T cells into IFN-γ- and IL17A-producing cells, and that both T-cell phenotypes are linked to GVHD. Conversely, ruxolitinib treatment in allo-HCT recipients increased FoxP3(+) regulatory T cells, which are linked to immunologic tolerance. Based on these results, we treated 6 patients with steroid-refractory GVHD with ruxolitinib. All patients responded with respect to clinical GVHD symptoms and serum levels of proinflammatory cytokines. In summary, ruxolitinib represents a novel targeted approach in GVHD by suppression of proinflammatory signaling that mediates tissue damage and by promotion of tolerogenic Treg cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Group Incompatibility / complications
  • Cells, Cultured
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Female
  • Graft vs Host Disease / drug therapy*
  • Graft vs Host Disease / etiology
  • Hematopoietic Stem Cell Transplantation / adverse effects
  • Humans
  • Janus Kinase 2 / antagonists & inhibitors*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Molecular Targeted Therapy
  • Nitriles
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyrazoles / therapeutic use*
  • Pyrimidines
  • Severity of Illness Index
  • Transplantation, Homologous / adverse effects
  • Treatment Outcome

Substances

  • Nitriles
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • ruxolitinib
  • Janus Kinase 2