HDAC inhibition and graft versus host disease - PubMed (original) (raw)

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HDAC inhibition and graft versus host disease

Sung Choi et al. Mol Med. 2011 May-Jun.

Abstract

Histone deacetylase (HDAC) inhibitors are currently used clinically as anticancer drugs. Recent data have demonstrated that some of these drugs have potent antiinflammatory or immunomodulatory effects at noncytotoxic doses. The immunomodulatory effects have shown potential for therapeutic benefit after allogeneic bone marrow transplantation in several experimental models of graft versus host disease (GVHD). These effects, at least in part, result from the ability of HDAC inhibitors (HDACi) to suppress the function of host antigen presenting cells such as dendritic cells (DC). HDACi reduce the dendritic cell (DC) responses, in part, by enhancing the expression of indoleamine 2,3-dioxygenase (IDO) in a signal transducer and activator of transcription-3 (STAT-3) dependent manner. They also alter the function of other immune cells such as T regulatory cells and natural killer (NK) cells, which also play important roles in the biology of GVHD. Based on these observations, a clinical trial has been launched to evaluate the impact of HDAC inhibitors on clinical GVHD. The experimental, mechanistic studies along with the brief preliminary observations from the ongoing clinical trial are discussed in this review.

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Figures

Figure 1

Figure 1

Acute GVHD of the skin. Photograph courtesy U of Michigan, BMT program.

Figure 2

Figure 2

Pathophysiology of GVHD. Three phases of GVHD pathophysiology. From: Reddy P, Ferrara JLM. (2009 Feb 28) Mouse models of graft-versus-host disease. In: StemBook [Internet]. Cambridge (MA): Harvard Stem Cell Institute; 2008–. Available at:

http://www.stembook.org/node/548

Figure 3

Figure 3

The regulation of immune cells by histone deacetylase inhibitors (HDACi). HDACi have direct and indirect effects on various immune cellular subsets: HDACi play an important role in the negative regulation of APCs, reduce the secretion of inflammatory cytokines, increase the numbers and function of naturally occurring regulatory T cells (Tregs), and activate natural killer (NK) cell–mediated activity.

Figure 4

Figure 4

The regulation of DCs by histone deacetylase inhibitors (HDACi).

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