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Timothy Powers Quinn, Robert B Nussenblatt, Baoying Liu; The Effect of HDACi Givinostat on the Expression of Immune Markers Related to Human Ocular Inflammation. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):883.
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© ARVO (1962-2015); The Authors (2016-present)
Uveitis involves swelling of the uvea, is responsible for 10-20% of blindness in the United States and is often attributable to an autoimmune disorder. Histone deacetylase inhibitor (HDACi) Givinostat, also known as ITF2357, prevents HDAC from altering a histone lysine residue leading to a condensed chromatin and has been shown to have an anti-inflammatory, anti-neoplastic and anti-angiogenic effect. It is currently in 11 phase II clinical trials and has been designated an orphan drug in the European Union for the treatment of juvenile idiopathic arthritis. Givinostat has been shown to inhibit expression of tumor necrosis factor α, interferon γ, interleukin 1α and β, and interleukin 6 and it as well has been shown to decrease inflammation in an experimental autoimmune uveoretinitis (EAU) murine model. We aimed to investigate the effects of Givinostat on the expression of immune markers related to ocular inflammation.
Human peripheral blood mononuclear cells (PBMCs) were isolated from whole blood samples and activated with either anti-CD3/CD28 or lippolysaccaride (LPS) and cultured with varying concentrations of Givinostat. Cultures activated with anti-CD3/CD28 were labeled with CD4, CD3 and either CD25 or CD28 and those activated with LPS labeled with CD16, CD14 and either CD163, CD80, CD86, or HLA-DR. Populations were then analyzed using flow cytometry FACScalibur and mean fluorescence intensity was assessed. Further, isolated CD4+ T cells were isolated and cultured with varying concentrations of Givinostat and with or without the presence of monocytes and labeled with CD4, CD3 and either CD25 or CD28 and analyzed as above.
A dose response curve effect was observed that decreased the expression of CD25, CD28, CD163, HLA-DR and CD80. Increasing Givinostat concentrations did not, however, decrease the expression of CD86. The observed dose response effect on CD25 and CD28 is independent of the presence of monocytes. Further, monocytes showed a greater degree of sensitivity to Givinostat as compared to T cells.
These results reveal an anti-inflammatory effect of Givinostat and as a potential treatment for autoimmune uveitis. This reveals a possibility to treat the disease at the level of epigenetics rather than symptomatically and further investigation into Givinostat is warranted.
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