Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease.
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.
III Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München, Germany; and.
Silvia
S
Spoerl
Department of Hematology, Oncology and Stem Cell Transplantation, and.
Nimitha R
NR
Mathew
III Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München, Germany; and.
Michael
M
Bscheider
Department of Pathology, University Medical Center Freiburg, Freiburg, Germany.
Annette
A
Schmitt-Graeff
Department of Hematology, Oncology and Stem Cell Transplantation, and.
Sophia
S
Chen
Department of Hematology, Oncology and Stem Cell Transplantation, and.
Tony
T
Mueller
III Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München, Germany; and.
Mareike
M
Verbeek
III Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München, Germany; and.
Julius
J
Fischer
III Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München, Germany; and.
Vera
V
Otten
III Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München, Germany; and.
Martina
M
Schmickl
Department of Hematology, Oncology and Stem Cell Transplantation, and.
Kristina
K
Maas-Bauer
Department of Hematology, Oncology and Stem Cell Transplantation, and.
Jürgen
J
Finke
III Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München, Germany; and.
Christian
C
Peschel
Department of Hematology, Oncology and Stem Cell Transplantation, and.
Justus
J
Duyster
III Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München, Germany; and.
Hendrik
H
Poeck
Department of Hematology, Oncology and Stem Cell Transplantation, and.
Robert
R
Zeiser
Department of Hematology, Oncology and Stem Cell Transplantation, and.
Nikolas
N
von Bubnoff
D000818:Animals; D001787:Blood Group Incompatibility / Q000150:complications; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000209:etiology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D009570:Nitriles; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines; D012720:Severity of Illness Index; D014184:Transplantation, Homologous / Q000009:adverse effects; D016896:Treatment Outcome
D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib; D053614:Janus Kinase 2