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JAK inhibition induces silencing of T Helper cytokine secretion and a profound reduction in T regulatory cells
Author(s) -
Keohane Clodagh,
Kordasti Shahram,
Seidl Thomas,
Perez Abellan Pilar,
Thomas Nicholas S. B.,
Harrison Claire N.,
McLornan Donal P.,
Mufti Ghulam J.
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.13519
Subject(s) - ruxolitinib , foxp3 , il 2 receptor , immunology , immune system , inflammation , cytokine , t cell , myelofibrosis , regulatory t cell , biology , medicine , cancer research , bone marrow
Summary CD 4 + T cells maintain cancer surveillance and immune tolerance. Chronic inflammation has been proposed as a driver of clonal evolution in myeloproliferative neoplasms ( MPN ), suggesting that T cells play an important role in their pathogenesis. Treatment with JAK inhibitors ( JAK i) results in improvements in MPN ‐associated constitutional symptoms as well as reductions in splenomegaly. However, effects of JAK i on T cells in MPN are not well established and the baseline immune signature remains unclear. We investigated the frequency and function of CD 4 + T cell subsets in 50 MPN patients at baseline as well as during treatment with either ruxolitinib or fedratinib in a subset. We show that CD 4 + CD 127 low CD 25 high FOXP 3 + T regulatory cells are reduced in MPN patients compared to healthy controls and that this decrease is even more pronounced following JAK i therapy. Moreover, we show that after 6 months of treatment the number of T helper (Th)‐17 cells increased. We also describe a functional ‘silencing’ of T helper cells both in vivo and in vitro and a blockade of pro‐inflammatory cytokines from these cells. This profound effect of JAK i on T cell function may underlay augmented rates of atypical infections that have been reported with use of these drugs.