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

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

Silvia Spoerl  1 , Nimitha R Mathew  2 , Michael Bscheider  1 , Annette Schmitt-Graeff  3 , Sophia Chen  2 , Tony Mueller  2 , Mareike Verbeek  1 , Julius Fischer  1 , Vera Otten  1 , Martina Schmickl  1 , Kristina Maas-Bauer  2 , Jürgen Finke  2 , Christian Peschel  1 , Justus Duyster  2 , Hendrik Poeck  1 , Robert Zeiser  2 , Nikolas von Bubnoff  2
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Free article

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

Silvia Spoerl et al. Blood. .
Free article

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.

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