title: JAK1/2 inhibition impairs T cell function in vitro and in patients with myeloproliferative neoplasms.
abstract: Ruxolitinib (INCB018424) is the first JAK1/JAK2 inhibitor approved for treatment of myelofibrosis. JAK/STAT-signalling is known to be involved in the regulation of CD4(+) T cells, which critically orchestrate inflammatory responses. To better understand how ruxolitinib modulates CD4(+) T cell responses, we undertook an in-depth analysis of CD4(+) T cell function upon ruxolitinib exposure. We observed a decrease in total CD3(+) cells after 3 weeks of ruxolitinib treatment in patients with myeloproliferative neoplasms. Moreover, we found that the number of regulatory T cells (Tregs), pro-inflammatory T-helper cell types 1 (Th1) and Th17 were reduced, which were validated by in vitro studies. In line with our in vitro data, we found that inflammatory cytokines [tumour necrosis factor-α (TNF), interleukin (IL)5, IL6, IL1B] were also downregulated in T cells from patients (all P < 0·05). Finally, we showed that ruxolitinib does not interfere with the T cell receptor signalling pathway, but impacts IL2-dependent STAT5 activation. These data provide a rationale for testing JAK inhibitors in diseases triggered by hyperactive CD4(+) T cells, such as autoimmune diseases. In addition, they also provide a potential explanation for the increased infection rates (i.e. viral reactivation and urinary tract infection) seen in ruxolitinib-treated patients.
authors.affiliation: Department of Internal Medicine III, Oncology, Haematology and Rheumatology, University Hospital Bonn (UKB), Bonn, Germany.
authors.forename: Sowmya
authors.initials: S
authors.lastname: Parampalli Yajnanarayana
authors.affiliation: Department of Stem Cell Transplantation, University Medical Centre Hamburg, Hamburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stübig
authors.affiliation: Department of Internal Medicine III, Oncology, Haematology and Rheumatology, University Hospital Bonn (UKB), Bonn, Germany.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cornez
authors.affiliation: Department of Stem Cell Transplantation, University Medical Centre Hamburg, Hamburg, Germany.
authors.forename: Haefaa
authors.initials: H
authors.lastname: Alchalby
authors.affiliation: Department of Internal Medicine III, Oncology, Haematology and Rheumatology, University Hospital Bonn (UKB), Bonn, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schönberg
authors.affiliation: Department of Internal Medicine III, Oncology, Haematology and Rheumatology, University Hospital Bonn (UKB), Bonn, Germany.
authors.forename: Janna
authors.initials: J
authors.lastname: Rudolph
authors.affiliation: Department of Stem Cell Transplantation, University Medical Centre Hamburg, Hamburg, Germany.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Triviai
authors.affiliation: Department of Stem Cell Transplantation, University Medical Centre Hamburg, Hamburg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Wolschke
authors.affiliation: Department of Internal Medicine III, Oncology, Haematology and Rheumatology, University Hospital Bonn (UKB), Bonn, Germany.
authors.forename: Annkristin
authors.initials: A
authors.lastname: Heine
authors.affiliation: Department of Internal Medicine III, Oncology, Haematology and Rheumatology, University Hospital Bonn (UKB), Bonn, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Brossart
authors.affiliation: Department of Stem Cell Transplantation, University Medical Centre Hamburg, Hamburg, Germany.
authors.forename: Nicolaus
authors.initials: N
authors.lastname: Kröger
authors.affiliation: Department of Internal Medicine III, Oncology, Haematology and Rheumatology, University Hospital Bonn (UKB), Bonn, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Wolf
mesh_terms: D000368:Aged; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D016130:Immunophenotyping; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D018655:Lymphocyte Count; D008875:Middle Aged; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D009570:Nitriles; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011948:Receptors, Antigen, T-Cell; D050799:STAT5 Transcription Factor; C540383:ruxolitinib; D053613:Janus Kinase 1; D053614:Janus Kinase 2
keywords: Janus kinases inhibitor; T cells; immunotherapy; myeloproliferative disease; ruxolitinib