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The Bromodomain and Extra-Terminal Protein Inhibitor OTX015 Suppresses T Helper Cell Proliferation and Differentiation.

Hu, X; Schewitz-Bowers, LP; Lait, PJP; Copland, DA; Stimpson, ML; Li, JJ; Liu, Y; ... Wei, L; + view all (2018) The Bromodomain and Extra-Terminal Protein Inhibitor OTX015 Suppresses T Helper Cell Proliferation and Differentiation. Current Molecular Medicine , 18 (9) pp. 594-601. 10.2174/1566524019666190126112238. Green open access

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Abstract

BACKGROUND: Dynamic epigenetic alterations accompanying CD4+ T helper cell differentiation have been implicated in multiple autoimmune diseases. The bromodomain and extra-terminal (BET) proteins are epigenetic regulators that recognize and bind to acetylated histones in chromatin and are targets for pharmacological inhibition. In this study we tested a new BET inhibitor under clinical development, OTX015, to interrogate its effects on key CD4+ T cell subsets associated with autoimmunity. METHODS: Naïve and memory murine and human CD4+ T cells were isolated and differentiated into populations characterized by the expression of interferon (IFN)-γ and interleukin (IL)-17. Cultured cells were then exposed to varying concentrations of OTX015 in vitro, and its impact on cytokine expression was quantified by flow cytometry. In parallel, the expression of the transcription factors TBX21 and RORC was quantified by PCR. A previously studied BET inhibitor JQ1 was used as a pharmacological control. RESULTS: OTX015 suppressed both murine and human CD4+ T cell proliferation. Its impact on cytokine expression varied in murine and human naïve and memory subsets. OTX015 was similarly effective as JQ1 in the suppression of cytokines and T helper cell proliferation. Higher concentrations of OTX015 also had a greater impact on the viability of murine versus human cells. IL-17 and IFN-γ expression was not altered in murine memory CD4+ T cells, whereas in human memory CD4+ T cells, OTX015 inhibited IL-17, but not IFN-γ. Across all human T cell subsets OTX015 suppressed IL-17 more effectively than IFN-γ. CONCLUSION: Our studies demonstrate that OTX015 has anti-inflammatory effects by suppressing murine and human CD4+ T cell proliferation and subset-dependent proinflammatory cytokine expression, including the selective suppression of IL-17 in human memory CD4+ T cells.

Type: Article
Title: The Bromodomain and Extra-Terminal Protein Inhibitor OTX015 Suppresses T Helper Cell Proliferation and Differentiation.
Location: Netherlands
Open access status: An open access version is available from UCL Discovery
DOI: 10.2174/1566524019666190126112238
Publisher version: https://doi.org/10.2174/1566524019666190126112238
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Autoimmune disease, CD4+ T cells, OTX015, antiproliferation, bromodomain and extraterminal domain (BET) inhibitors, epigenetics, immunosuppression
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10068127
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