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Lauren P Schewitz-Bowers, Philippa J P Lait, Wei Chen, Ester Carreno, Xiao Hu, Zhiyu Li, Jing Chen, Kara M Ponsford, Andrew D Dick, Lai Wei, Rachel R Caspi, Richard W J Lee, Benjamin Chaigne-Delalande; The suppressive effect of the epigenetic drug, Givinostat (ITF2357), on peripheral blood leukocytes from uveitis patients. Invest. Ophthalmol. Vis. Sci. 2017;58(8):510.
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Epigenetic modulation of histone and non-histone proteins plays a key role in regulating gene transcription. Histone acetylation is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). In recent years, HDAC inhibitors (HDACi) have emerged as potential therapeutics for reversing aberrant epigenetic changes, particularly as antitumor agents. At lower concentrations, HDACi's have been shown to be anti-inflammatory and are thus gaining interest within the immunology field. Givinostat (ITF2357) is a pan-HDACi that is efficacious in refractory leukaemias. Little is known about the effects of Givinostat in an autoimmune setting. Therefore, we tested its effects in leukocytes from healthy controls and non-infectious uveitis patients.
CD4+ T cells isolated from healthy controls (n=6) and uveitis patients (Sarcoidosis, Behçets and VKH; n=14) were cultured with anti CD3/CD28 and Givinostat (50-200nM). Post culture proliferation, cytokine production (IL-17, IFN-y, IL-4, IL-10, IL-22 and GM-CSF), activation status, FoxP3 and Helios expression were analysed by flow cytometry. Additionally, the effect of increasing doses of Givinostat was investigated in Lipopolysaccharide (LPS)-stimulated CD14+ monocytes from healthy controls.
Givinostat (200nM) inhibited the proliferation of CD4+ T cells from healthy controls (43.6% ±17.8) and uveitis patients (32.2% ±14.4) and suppressed expression of the markers, CD25 and Ki67. Furthermore, Givinostat treatment reduced IL-17 expression in both cohorts (41.7% ±23.2 for healthy controls and 50.3% ± 34.9 for uveitis patients), but to a lesser extent for IFN-γ (14.4% ±22.1 for healthy controls and 19.23% ±21.7 for uveitis patients). Conversely FoxP3 expression increased and there was also an increase in Helios expression within thymically derived T regulatory cells. Finally, LPS stimulated monocytes from healthy controls showed a modified phenotype in response to Givinostat (decreased activation as seen by CD80, CD14 and HLA-DR).
These data demonstrate that in in vitro human cultures, Givinostat has an anti-proliferative and anti-inflammatory effect on T cells and monocytes, suggesting that this pan-HDACi has translational potential as a novel therapy for inflammatory eye disease.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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