title: Histone deacetylase inhibitors induce antigen specific anergy in lymphocytes: a comparative study.
abstract: Induction of immune tolerance to transplanted tissue continues to be a challenge for organ transplantation. In the present study, six widely used histone deacetylase inhibitors (HDAI), sodium butyrate (n-butyrate), Trichostatin A, Oxamflatin, Scriptaid, HDAC I and HDAC III, were examined for ability to induce antigen-specific immune anergy in cloned and naïve murine CD4(+) T cells. When first compared for their ability to inhibit histone deacetylation Trichostatin A was found to be 10 times more potent than HDAC III, Oxamflatin and Scriptaid and 10(4) times more potent than n-butyrate. When we compared ability to inhibit CD4(+) T cell proliferation in response to IL-2 stimulation, Trichostatin A was the most potent with 100% inhibition using 100 nM Trichostatin A, while 1 muM of HDAC III, Oxamflatin and Scriptaid and 1 mM of n-butyrate were required for this effect. When the tolerogenic activity of Trichostatin A, Scriptaid and n-butyrate were compared using cloned Th1 cells specific for keyhole limpet hemocyanin (KLH), all three HDAI were effective, but Trichostatin A was again the most potent. Finally, Trichostatin A (0.05 mM) was shown to induce anergy in OT-II ovalbumin-specific naïve CD4(+) T-cells. We concluded that Trichostatin A was the most potent HDAI with regard to inhibition of histone deacetylation and the ability to induce antigen-specific anergy in both cloned and naïve CD4(+) T cells. These results will guide future studies examining HDAIs for ability to induce clinical tolerance in organ transplantation.
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, AR, USA. edensrerik@uams.edu <edensrerik@uams.edu>
authors.forename: R Erik
authors.initials: RE
authors.lastname: Edens
authors.forename: Selma
authors.initials: S
authors.lastname: Dagtas
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Gilbert
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D017635:Clonal Anergy; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006433:Hemocyanins / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018417:Th1 Cells / Q000276:immunology
chemical_list: D000941:Antigens; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D007376:Interleukin-2; D007371:Interferon-gamma; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin