Deacetylase inhibition increases regulatory T cell function and decreases incidence and severity of collagen-induced arthritis.
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.
Saouaf
Sandra J
SJ
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104-6082, USA.
Li
Bin
B
Zhang
Geng
G
Shen
Yuan
Y
Furuuchi
Narumi
N
Hancock
Wayne W
WW
Greene
Mark I
MI
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000187:drug effects; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D014635:Valproic Acid / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid; D006655:Histone Deacetylases