Journal
BRITISH JOURNAL OF HAEMATOLOGY
Volume 169, Issue 6, Pages 824-833Publisher
WILEY-BLACKWELL
DOI: 10.1111/bjh.13373
Keywords
myeloproliferative disease; T cells; immunotherapy; ruxolitinib; Janus kinases inhibitor
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Funding
- Deutsche Forschungsgemeinschaft [DFG WO1877/1-1]
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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 3weeks 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 invitro studies. In line with our invitro data, we found that inflammatory cytokines [tumour necrosis factor- (TNF), interleukin (IL)5, IL6, IL1B] were also downregulated in T cells from patients (all P<005). 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.
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