The histone deacetylase inhibitor trichostatin A upregulates regulatory T cells and modulates autoimmunity in NZB/W F1 mice.
We sought to determine if the histone deacetylase inhibitor (HDI), trichostatin A (TSA), would alter systemic lupus erythematosus (SLE) in NZB/W mice. Fourteen to sixteen-week-old female NZB/W F1 mice were given TSA (1.0mg/kg body weight (BW)) intraperitonealy (i.p.) daily, TSA (1.0mg/kg BW) i.p.+anti-CD25 (250mg/mouse) i.p. every third day, only anti-CD25 (250mg/mouse) i.p., DMSO or isotype IgG. Disease progression was assessed as they aged. Mice were sacrificed at 26 or 38 weeks of age, tissues collected and evaluated. At 36 weeks, TSA-treated animals had decreased anti-double stranded DNA (dsDNA) autoantibodies and decreased protein excretion compared to controls. Spleen size and the percentage of CD4+CD69+ cells were decreased, with an increase in CD4+CD25+ T cells in the TSA-treated mice. Real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis of T cells showed a decrease in IL-6 production but an increase in TGF-beta1 and Foxp3 in the TSA-treated animals. Kidney analysis showed a decrease in IgG and C3 deposition, decrease in pathologic glomerular disease and renal MCP-1, MMP-9, and IL-6 mRNA expression. Anti-CD25-treated mice euthanized at 26 weeks of age showed decreased Foxp3+CD4+CD25+ T cells compared to TSA-treated mice. These data suggest TSA administration modulates lupus-like disease, in part, by increasing T regulatory cells.
Reilly
Christopher M
CM
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, VA, USA. chreilly@vcom.vt.edu
Thomas
Megan
M
Gogal
Robert
R
Olgun
Selen
S
Santo
Arben
A
Sodhi
Renna
R
Samy
Eileen T
ET
Peng
Stanford L
SL
Gilkeson
Gary S
GS
Mishra
Nilamadhab
N
D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D015551:Autoimmunity / Q000187:drug effects; D015704:CD4 Antigens / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007155:Immunologic Factors / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007668:Kidney / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D051379:Mice; D008814:Mice, Inbred NZB; D009929:Organ Size; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D000974:Antibodies, Antinuclear; D015704:CD4 Antigens; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007155:Immunologic Factors; D053645:Interleukin-2 Receptor alpha Subunit; C012589:trichostatin A