Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease
| Autor: | Jürgen Finke, Tony A. Mueller, Sophia Chen, Mareike Verbeek, Julius C. Fischer, Michael Bscheider, Annette Schmitt-Graeff, Nikolas von Bubnoff, Hendrik Poeck, Christian Peschel, Vera Otten, Silvia Spoerl, Martina Schmickl, Justus Duyster, Nimitha R. Mathew, Kristina Maas-Bauer, Robert Zeiser |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Ruxolitinib medicine.medical_treatment Immunology Drug Evaluation Preclinical Graft vs Host Disease chemical and pharmacologic phenomena Severity of Illness Index Biochemistry Proinflammatory cytokine Mice immune system diseases Nitriles medicine Animals Humans Transplantation Homologous Molecular Targeted Therapy Protein Kinase Inhibitors Cells Cultured Mice Inbred BALB C Janus kinase 2 Janus kinase 1 biology business.industry Hematopoietic Stem Cell Transplantation FOXP3 Cell Biology Hematology Janus Kinase 2 medicine.disease Mice Inbred C57BL Transplantation Disease Models Animal Pyrimidines Treatment Outcome surgical procedures operative Graft-versus-host disease Cytokine Blood Group Incompatibility biology.protein Pyrazoles Female business medicine.drug |
| Zdroj: | Blood. 123:3832-3842 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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