JAK1/2 inhibition impairs T cell function in vitro and in patients with myeloproliferative neoplasms

Br J Haematol. 2015 Jun;169(6):824-33. doi: 10.1111/bjh.13373. Epub 2015 Mar 30.

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.

Keywords: Janus kinases inhibitor; T cells; immunotherapy; myeloproliferative disease; ruxolitinib.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cell Differentiation / drug effects
  • Cell Differentiation / immunology
  • Cell Proliferation / drug effects
  • Cytokines / biosynthesis
  • Humans
  • Immunophenotyping
  • Janus Kinase 1 / antagonists & inhibitors*
  • Janus Kinase 1 / metabolism
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / metabolism
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Lymphocyte Count
  • Middle Aged
  • Myeloproliferative Disorders / drug therapy
  • Myeloproliferative Disorders / immunology*
  • Myeloproliferative Disorders / metabolism
  • Phenotype
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use
  • Receptors, Antigen, T-Cell / metabolism
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • T-Lymphocyte Subsets / drug effects
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism

Substances

  • Cytokines
  • INCB018424
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Receptors, Antigen, T-Cell
  • STAT5 Transcription Factor
  • Janus Kinase 1
  • Janus Kinase 2