Specific HDAC6 inhibition by ACY-738 reduces SLE pathogenesis in NZB/W mice (THER6P.858)

Abstract

Abstract Histone deacetylase inhibitors are important modifiers of gene and protein expression. In our studies, we sought to determine if a specific HDAC6 inhibitor (ACY-738) was able to decrease disease in NZB/W lupus-prone mice through regulation of B and T cell differentiation. From 22 - 38 weeks-of-age, NZB/W mice were injected intraperitoneally with 20 mg/kg of ACY-738, 5 mg/kg of ACY-738, or DMSO (vehicle control). Body weight and proteinuria were measured every 2 weeks, while sera anti-dsDNA, Ig isotypes, and cytokine levels were measured every 4 weeks. Kidney disease was determined using sera and urinary markers of SLE, immune complex deposition, and renal pathology. Flow cytometric analysis was used to assess thymic and splenic T cell profiles as well as bone marrow, splenic, and peripheral B cell differentiation patterns. Our results showed that HDAC6 inhibition was able to decrease many hallmarks of SLE disease including splenomegaly, immune complex-mediated glomerulonephritis, sera anti-dsDNA levels, and inflammatory cytokine production. ACY-738 treatment decreased the number of double-negative thymic T cells and increased the percentage of splenic Treg cells. Inhibition of HDAC6 altered BM B cell differentiation by increasing 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.