1. JAK1/2 inhibition impairs T cell function in vitro and in patients with myeloproliferative neoplasms.
- Author
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Parampalli Yajnanarayana, Sowmya, Stübig, Thomas, Cornez, Isabelle, Alchalby, Haefaa, Schönberg, Kathrin, Rudolph, Janna, Triviai, Ioanna, Wolschke, Christine, Heine, Annkristin, Brossart, Peter, Kröger, Nicolaus, and Wolf, Dominik more...
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JANUS kinases ,T helper cells ,MYELOPROLIFERATIVE neoplasms ,MYELOFIBROSIS ,TUMOR necrosis factors ,INTERLEUKINS ,THERAPEUTICS - 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. [ABSTRACT FROM AUTHOR] more...- Published
- 2015
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