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JAK1/2 inhibition impairs T cell function in vitro and in patients with myeloproliferative neoplasms
Author(s) -
Parampalli Yajnanarayana Sowmya,
Stübig Thomas,
Cornez Isabelle,
Alchalby Haefaa,
Schönberg Kathrin,
Rudolph Janna,
Triviai Ioanna,
Wolschke Christine,
Heine Annkristin,
Brossart Peter,
Kröger Nicolaus,
Wolf Dominik
Publication year - 2015
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.13373
Subject(s) - ruxolitinib , myelofibrosis , cancer research , medicine , immunology , t cell , jak stat signaling pathway , receptor , immune system , bone marrow , tyrosine kinase
Summary Ruxolitinib ( INCB 018424) is the first JAK 1/ JAK 2 inhibitor approved for treatment of myelofibrosis. JAK / STAT ‐signalling is known to be involved in the regulation of CD 4 + T cells, which critically orchestrate inflammatory responses. To better understand how ruxolitinib modulates CD 4 + T cell responses, we undertook an in‐depth analysis of CD 4 + T cell function upon ruxolitinib exposure. We observed a decrease in total CD 3 + 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, IL 6, IL 1B] 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 IL 2‐dependent STAT 5 activation. These data provide a rationale for testing JAK inhibitors in diseases triggered by hyperactive CD 4 + 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.