We sought to determine if a specific class I and II HDAC inhibitor (ITF2357) was able to decrease disease in lupus-prone NZB/W mice through regulation of T cell profiles. From 22 - 38 weeks-of-age, NZB/W and non-lupus NZW mice were treated with ITF2357 (5 mg/kg or 10 mg/kg), or 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 IgG levels, immune complex deposition, and renal pathology. T lymphocyte profiles were assessed using flow cytometric analyses. Our results showed NZB/W mice treated with the high-dose of ITF2357 had decreased renal disease and inflammatory cytokines in the sera. Treatment with ITF2357 decreased the Th17 phenotype while increasing the percentage of Tregs as well as Foxp3 acetylation. These results suggest that specific HDAC inhibition may decrease disease by altering T cell differentiation and acetylation.

We sought to determine if a selective HDAC6 inhibitor (ACY-738) decreases disease in NZB/W mice. From 22 to 38weeks-of-age, mice were injected intraperitoneally with 5 or 20mg/kg of ACY-738, or vehicle control. Body weight and proteinuria were measured every 2weeks, while sera anti-dsDNA, Ig isotypes, and cytokine levels were measured every 4weeks. Kidney disease was determined by evaluation of sera, urine, immune complex deposition, and renal pathology. Flow cytometric analysis assessed thymic, splenic, bone marrow, and peripheral lymphocyte differentiation patterns. Our results showed HDAC6 inhibition decreased SLE disease by inhibiting immune complex-mediated glomerulonephritis, sera anti-dsDNA levels, and inflammatory cytokine production and increasing splenic Treg cells. Inhibition of HDAC6 increased the percentage of cells in the early-stage developmental fractions of both pro- and pre-B cells. These results suggest that specific HDAC6 inhibition may be able to decrease SLE disease by altering aberrant T and B cell differentiation.

Chromosomal translocations typically impair cell differentiation and often require secondary mutations for malignant transformation. However, the role of a primary translocation in the development of collaborating mutations is debatable. To delineate the role of leukemic translocation NUP98-HOXD13 (NHD13) in secondary mutagenesis, DNA break and repair mechanisms in stimulated mouse B lymphocytes expressing NHD13 were analyzed. Our results showed significantly reduced expression of non-homologous end joining (NHEJ)-mediated DNA repair genes, DNA Pkcs, DNA ligase4, and Xrcc4 leading to cell cycle arrest at G2/M phase. Our results showed that expression of NHD13 fusion gene resulted in impaired NHEJ-mediated DNA break repair.

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