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

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

Research output: Contribution to journalArticlepeer-review

318 Scopus citations

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.

Original languageEnglish
Pages (from-to)3832-3842
Number of pages11
JournalBlood
Volume123
Issue number24
DOIs
StatePublished - 12 Jun 2014
Externally publishedYes

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