Histone deacetylase inhibition by ITF2357 reduces SLE pathogenesis in vivo (P5161)

Abstract

Abstract Histone deacetylase (HDAC) inhibitors are important modifiers of gene and protein expression. In our studies, we sought to determine if a specific HDAC I and II inhibitor (ITF2357) was able to decrease disease in lupus-prone New Zealand Black/White (NZB/W) F1 female mice through regulation of T cell profiles. From 22 - 38 weeks-of-age, NZB/W and non-lupus New Zealand White (NZW) mice were injected intraperitoneally with 10mg/kg of ITF2357 (high dose), 5mg/kg of ITF2357 (low-dose), or the vehicle control. Body weight and proteinuria were measured every 2 weeks, while sera anti-dsDNA and cytokine levels were measured every 4 weeks. Kidney disease was determined by sera BUN and creatinine, immune complex deposition, and renal pathology. T lymphocyte profiles were assessed using flow cytometric analyses and T regulatory cell function was determined by CFSE assay. Our results showed NZB/W mice treated with the high-dose of ITF2357 had increased histone acetylation resulting in a decrease in overall renal disease and inflammatory cytokines in the sera. Treatment with ITF2357 at 10 mg/kg decreased the Th17 phenotype while increasing the percentage and function of Treg cells as well as Foxp3 acetylation. These results suggest that specific HDAC inhibition may decrease disease by altering T cell differentiation and function.