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

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)- 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. Higher concentrations of OTX015 also had a greater impact on the viability of murine versus human cells. IL-17 and IFN- expression was not altered in murine memory CD4 + T cells, whereas in human memory CD4 + T cells, OTX015 inhibited IL-17, but not IFN-. Across all human T cell subsets OTX015 suppressed IL-17 more effectively than IFN-. Conclusion: Our studies demonstrate that OTX015 has anti-inflammatory effects by suppressing murine and human CD4 + T cell proliferation and subsetdependent proinflammatory cytokine expression, including the selective suppression of IL-17 in human memory CD4 + T cells.

Epigenetic drug screen identified IOX1 as an inhibitor of Th17-mediated inflammation through targeting TET2

“…Previous studies report histone deacetylase (HDAC) inhibitors, 8 , 9 bromodomain antagonists, 10 , 11 , 12 , 13 , 14 and histone H3K27me3 demethylase inhibitors 15 can reduce CD4 + T cell mediated inflammation. Similarly, previous work from our laboratory demonstrates how the DNA methyltransferase inhibitor Zebularine 16 and the Bromodomain and Extra-Terminal Protein Inhibitor OTX015 17 can both suppress Th17 mediated inflammation. However, systemic toxicity and low specificity in patients limits the potential for clinical application of these drugs.…”

“…Further investigations using OTX015 (a new BET inhibitor) demonstrated in vitro suppression of both proliferation and subset-dependent proinflammatory cytokine expression in murine and human CD4 + T cells, including selective suppression of IL-17 in human memory CD4 + cells. 17 Then we focused on evaluation of IOX1, a potent and broad-spectrum inhibitor of 2OG oxygenases, including the JmjC demethylases and DNA demethylases ( Fig. 2 a).…”

New Insights into Epigenetic Regulation of T Cell Differentiation

“…The contradiction between the two reports, i.e., Th-1 and Th-2 production [ 43 ] vs. Th-17 cells [ 44 ] generation due to Cxxc1 ablation, might be due to the Cre system ( ER-Cre vs. dLck-Cre ) that was used as the former targets mature T cells whereas the latter acts on immature pre-selection thymocytes. Another study tested the effects of a new BET (bromodomain and extra-terminal) inhibitor, OTX015, on CD4 + Th-17 cells [ 72 ]. BET proteins are epigenetic regulators that recognize and bind to acetylated histones in chromatin and that regulate gene expression.…”

“…BET proteins are epigenetic regulators that recognize and bind to acetylated histones in chromatin and that regulate gene expression. The authors showed that OTX015 has anti-inflammatory effects via suppression of CD4 + T cell proliferation in both mice and humans and suppresses the production of Th-17 cytokines (IL-17 in particular) in humans [ 72 ]. These data suggest that BET plays an important role in CD4 + Th-17 cell generation and persistence.…”

Novel epigenetic therapy for Th17 cell mediated autoimmune inflammatory diseases

“… 4 Previously DNA methyltransferase inhibitor, Zebularine and bromodomain, and extra-terminal (BET) protein inhibitor, OTX015 have been reported to suppress the Th17 cell mediated autoimmune uveitis in experimental animal models. 5 , 6 Although these drugs show undesirable systemic toxicity with suboptimal specificity, they indicate the clinical applicability of epigenetics as a novel treatment for autoimmune uveitis. 7 , 8 …”