Histone deacetylase inhibitors induce antigen specific anergy in lymphocytes: A comparative study

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 104 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 μM 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.