HDACi and Foxp3 Tregs

The clinical use of many pan-HDACi is associated with a common adverse effect profile of cardiac QT prolongation, nausea, diarrhea, vomiting, hypokalemia, loss of appetite and thrombocytopenia, plus in many cases, profound and debilitating fatigue. Likewise, their ability to induce cytotoxicity is considered a key and highly desirable action in the context of malignancies, which often overexpress HDAC1 and HDAC2, but the toxicity profile and cytotoxic effects render these agents far less suitable for nononcologic applications. To that end, various groups are seeking to avoid the class-associated side effects of pan-HDACi by trying to design isoform-selective HDACi for use in oncology and inflammation.

Our focus on selective HDACi arose from our findings in testing several HDACi compounds for their effects in murine models of colitis, including dextran sodium sulfate (DSS)-induced colitis and the T-cell-dependent CD45RBhi adoptive transfer model (Tao et al. 2007; de Zoeten et al. 2010). Two pan-HDACi compounds, trichostatin-A (TsA) and suberoylanilide hydroxamic acid (SAHA), but not MS275, a potent and long-acting HDAC class I-specific inhibitor, blocked development of colitis as shown by prevention of weight loss and associated blood in the stool, diarrhea, and histologic injury. Likewise, in T-cell-dependent adoptive transfer models, both pan-HDACi but not MS275 were effective in preventing the development of colitis, and in promoting the resolution of established colitis. The beneficial effects of pan-HDACi were dependent upon the presence of Foxp3+ T regulatory (Treg) cells, since Treg depletion or use of Scurfy mice with a mutation in Foxp3 abrogated any therapeutic benefit of HDACi administration (de Zoeten et al. 2010). Foxp3+ Tregs play a key part in limiting autoimmunity and maintaining peripheral tolerance, and mutations of Foxp3 lead to lethal autoimmunity in humans and mice (Brunkow et al. 2001; Bennett et al. 2001; Hori et al. 2003; Fontenot et al. 2003; Khattri et al. 2003). In wild-type (WT) mice, pan-HDACi but not MS275 use decreased mucosal inflammatory cytokine production, and increased Foxp3 and anti-inflammatory cytokine expression, and enhanced Treg suppressive function (Tao et al. 2007; de Zoeten et al. 2010).

Further in vitro analysis (Wang et al. 2009b) demonstrated that multiple pan-HDACi hydroxamates such as TsA, SAHA, M344 and Scriptaid were effective in low nanomolar levels at enhancing murine Treg function, as well as the suppressive functions of rhesus macaque (Johnson et al. 2008) and human (Akimova et al. 2010) Treg cells. Additional pan-HDACi, such as the short-chain fatty acids, phenyl-butyrate and valproic acid, also enhanced murine Treg function, but were only active in the micromolar and millimolar ranges, respectively. Our findings with regard to TsA-induced in vivo expansion of Foxp3+ Treg numbers and function were confirmed by other groups (Reilly et al. 2008; Koenen et al. 2008; Moon et al. 2009; Lei et al. 2010), as was the induction of Foxp3 using other HDACi, such as SAHA (Lucas et al. 2009). In contrast to our data using pan-HDACi, we found that class I-specific HDACi, such as the benzamides, MS275 and MC1293, and the quinolinol, NSC3852, lacked any effect on Treg functions in vitro when used at micromolar or higher levels (de Zoeten et al. 2010; Wang et al. 2009b). Hence, at least when using standard therapeutic dosages, only agents that blocked both class I and class II HDACs were effective at enhancing Treg function, and since class I-selective HDACi compounds were ineffective in the same assays, our data point to a key role for class II HDAC in control of Treg functions.

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