Histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect.

Department of Internal Medicine, University of Michigan Cancer Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0942, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 04/2004; 101(11):3921-6. DOI: 10.1073/pnas.0400380101
Source: PubMed

ABSTRACT Acute graft-versus-host disease (GVHD) and leukemic relapse are the two major obstacles to successful outcomes after allogeneic bone marrow transplantation (BMT), an effective therapy for hematological malignancies. Several studies have demonstrated that the dysregulation of proinflammatory cytokines and the loss of gastrointestinal tract integrity contribute to GVHD, whereas the donor cytotoxic responses are critical for graft-versus-leukemia (GVL) preservation. Suberoylanilide hydroxamic acid (SAHA) is currently in clinical trials as an antitumor agent; it inhibits the activity of histone deacetylases and at low doses exhibits antiinflammatory effects by reducing the production of proinflammatory cytokines. Using two well characterized mouse models of BMT, we have studied the effects of SAHA on GVHD severity and GVL activity. Administration of SAHA from day +3 to day +7 after BMT reduced serum levels of the proinflammatory cytokines and decreased intestinal histopathology, clinical severity, and mortality from acute GVHD compared with vehicle-treated animals. However, SAHA had no effect on donor T cell proliferative and cytotoxic responses to host antigens in vivo or in vitro. When mice received lethal doses of tumor cells at the time of BMT, administration of SAHA did not impair GVL activity and resulted in significantly improved leukemia-free survival by using two different tumor and donor/recipient combinations. These findings reveal a critical role for histone deacetylase inhibition in the proinflammatory events contributing to GVHD and suggest that this class of pharmacologic agents may provide a strategy to reduce GVHD while preserving cytotoxic T cell responses to host antigens and maintaining beneficial GVL effects.

  • [Show abstract] [Hide abstract]
    ABSTRACT: We examined immunological responses in patients receiving histone deacetylase (HDAC) inhibition (vorinostat) for graft-versus-host disease (GVHD) prophylaxis following allogeneic hematopoietic cell transplant (allo-HCT). Vorinostat treatment increased histone acetylation in peripheral blood mononuclear cells (PBMC) from treated patients, confirming target HDAC inhibition. HDAC inhibition reduced pro-inflammatory cytokine levels in plasma and from PBMC, decreased ex vivo responses of PBMC to pro-inflammatory TLR-4 stimuli, but did not alter the number or response of conventional T cells (Tconv) to non-specific stimuli. However, the numbers of regulatory T cells (Tregs) were increased, which revealed greater demethylation of the Foxp3 T regulatory-specific demethylation region. Vorinostat-treated patients showed increased expression of CD45RA and CD31 on Tregs, and these Tregs demonstrated greater suppression on a per-cell basis. Consistent with preclinical findings, HDAC inhibition also increased STAT-3 acetylation and induced indoleamine-2,3-dioxygenase (IDO). Our data demonstrate that HDAC inhibition reduces inflammatory responses of PBMC but enhances Tregs after allo-HCT. Copyright © 2014 American Society of Hematology.
    Blood 11/2014; 125(5). DOI:10.1182/blood-2014-10-605238 · 9.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: ITF2357 (generic givinostat) is an orally active, hydroxamic-containing histone deacetylase (HDAC) inhibitor, with broad anti-inflammatory properties and which has been used to treat children with systemic juvenile idiopathic arthritis. ITF2357 inhibits both Class I and II HDACs, reduces caspase 1 activity in human peripheral blood mononuclear cells (PBMC) and the secretion of IL 1β and other cytokines at 25-100 nM; at concentrations >200nM, ITF2357 is toxic in vitro. ITF3056, an analogue of ITF2357, inhibits only HDAC8 (IC50 285 nM). Here we compared the production of IL 1β, IL 1α, TNFα and IL 6 by ITF2357 to that of ITF3056 in PBMC stimulated with lipopolysaccharide (LPS), heat-killed Candida albicans or anti-CD3/anti-CD28 antibodies. ITF3056 reduced LPS-induced cytokines from 100 to 1000 nM; at 1000 nM, the secretion of IL 1β was reduced by 76%, TNFα by 88% and IL 6 by 61%. The intracellular levels of IL 1α were 30% lower. There was no evidence of cell toxicity at concentrations of ITF3056 (100 to 1000nM). Gene expression of TNFα was markedly reduced (80%) whereas IL 6 gene expression was 40% lower. Although anti-CD3/28 and Candida stimulation of IL 1β and TNFα was modestly reduced, IFNγ production was 75% lower. Mechanistically, ITF3056 reduced the secretion of processed IL 1β independent of inhibition of caspase 1 activity; however, synthesis of the IL 1β precursor was reduced by 40% without significant decrease in IL 1β mRNA levels. In mice, ITF3056 reduced LPS-induced serum TNFα by 85% and IL 1β by 88%. These data suggest that specific inhibition of HDAC8 results in reduced inflammation without cell toxicity. Copyright © 2014, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 12/2014; 290(4). DOI:10.1074/jbc.M114.618454 · 4.60 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Broad-spectrum histone deacetylase (HDAC) inhibitors are useful in the treatment of allergic and autoimmune diseases and malignancy. However, use of more specific HDAC inhibitors might limit the toxicities caused by HDAC inhibition. HDAC6, a member of the HDAC family, is highly expressed on CD8 T cells and has been shown to regulate immune responses through interactions between T cells and antigen-presenting cells. However, the mechanism by which HDAC6 inhibition affects the activation and functions of CD8 T cells is unclear. We investigated the role or roles of HDAC6 in CD8 T-cell activation and functions during skin inflammation in vitro and in vivo and examined the mechanism by which HDAC6 inhibition modifies T-cell receptor signaling in vitro. We assessed the clinical and biological effects of ACY-1215, an HDAC6-specific inhibitor, by using murine CD8 T cell-related skin disease models, including contact hypersensitivity (CHS) and experimental graft-versus-host disease (GVHD)-like disease. ACY-1215, an HDAC6 inhibitor, prevented the development of CHS and GVHD-like disease in vivo by modulating CD8 T-cell activation and functions; abrogated the induction of effector T cells from naive CD8 T cells by means of anti-CD3/CD28 antibody- or antigen-specific stimulation in vitro; and enhanced the binding of acetylated heat shock protein 90 to lymphocyte-specific protein tyrosine kinase in vitro, disrupting lymphocyte-specific protein tyrosine kinase phosphorylation and leading to impairment of the mitogen-activated protein kinase pathway. HDAC6, a key modifier of T-cell receptor signaling, might represent a novel target for the treatment of CD8 T cell-related skin diseases, including CHS and GVHD. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
    Journal of Allergy and Clinical Immunology 11/2014; 135(5). DOI:10.1016/j.jaci.2014.10.002 · 11.25 Impact Factor