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Deacetylase inhibition increases regulatory T cell function and decreases incidence and severity of collagen-induced arthritis

2009; Elsevier BV; Volume: 87; Issue: 2 Linguagem: Inglês

10.1016/j.yexmp.2009.06.003

1096-0945

Sandra J. Saouaf, Bin Li, Geng Zhang, Yuan Shen, Narumi Furuuchi, Wayne W. Hancock, Mark I. Greene,

T-cell and B-cell Immunology

Collagen-induced arthritis (CIA) is an established mouse model of disease with hallmarks of clinical rheumatoid arthritis. Histone/protein deacetylase inhibitors (HDACi) are known to inhibit the pathogenesis of CIA and other models of autoimmune disease, although the mechanisms responsible are unclear. Regulatory T cell (Treg) function is defective in rheumatoid arthritis. FOXP3 proteins in Tregs are present in a dynamic protein complex containing histone acetyltransferase and HDAC enzymes, and FOXP3 itself is acetylated on lysine residues. We therefore investigated the effects of HDACi therapy on regulatory T cell function in the CIA model. Administration of an HDACi, valproic acid (VPA), significantly decreased disease incidence (p < 0.005) and severity (p < 0.03) in CIA. In addition, VPA treatment increased both the suppressive function of CD4+CD25+ Tregs (p < 0.04) and the numbers of CD25+FOXP3+ Tregs in vivo. Hence, clinically approved HDACi such as VPA may limit autoimmune disease in vivo through effects on the production and function of FOXP3+ Treg cells.