The histone deacetylase inhibitor trichostatin A upregulates regulatory T cells and modulates autoimmunity in NZB/W F1 mice

Abstract 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 (1.0 mg/kg body weight (BW)) intraperitonealy (i.p.) daily, TSA (1.0 mg/kg...

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Bibliographic Details
Published in:Journal of autoimmunity 2008-09, Vol.31 (2), p.123-130
Main Authors: Reilly, Christopher M, Thomas, Megan, Gogal, Robert, Olgun, Selen, Santo, Arben, Sodhi, Renna, Samy, Eileen T, Peng, Stanford L, Gilkeson, Gary S, Mishra, Nilamadhab
Format: Article
Language:English
Subjects:
Allergy and Immunology
Animals
Antibodies, Antinuclear - blood
Autoimmunity
Autoimmunity - drug effects
CD4 Antigens - metabolism
Disease Models, Animal
Disease Progression
Female
Flow Cytometry
Histone Deacetylase Inhibitors
Hydroxamic Acids - pharmacology
Immunologic Factors - pharmacology
Interleukin-2 Receptor alpha Subunit - metabolism
Kidney - pathology
Lupus Erythematosus, Systemic - blood
Lupus Erythematosus, Systemic - drug therapy
Lupus Erythematosus, Systemic - immunology
Lupus nephritis
Mice
Mice, Inbred NZB
Mouse model
NZB/NZW
Organ Size
T-Lymphocytes, Regulatory - drug effects
T-Lymphocytes, Regulatory - immunology
Treg cell
Up-Regulation - drug effects
Up-Regulation - immunology
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Summary:Abstract 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 (1.0 mg/kg body weight (BW)) intraperitonealy (i.p.) daily, TSA (1.0 mg/kg BW) i.p. + anti-CD25 (250 mg/mouse) i.p. every third day, only anti-CD25 (250 mg/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-β1 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.
ISSN:0896-8411
1095-9157
DOI:10.1016/j.jaut.2008.04.020