Histone deacetylase inhibition regulates inflammation and enhances Tregs after allogeneic hematopoietic cell transplantation in humans

Blood. 2015 Jan 29;125(5):815-9. doi: 10.1182/blood-2014-10-605238. Epub 2014 Nov 26.

Abstract

We examined immunological responses in patients receiving histone deacetylase (HDAC) inhibition (vorinostat) for graft-versus-host disease prophylaxis after allogeneic hematopoietic cell transplant. Vorinostat treatment increased histone acetylation in peripheral blood mononuclear cells (PBMCs) from treated patients, confirming target HDAC inhibition. HDAC inhibition reduced proinflammatory cytokine levels in plasma and from PBMCs and decreased ex vivo responses of PBMCs to proinflammatory TLR-4 stimuli, but did not alter the number or response of conventional T cells to nonspecific 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 signal transducer and activator of transcription 3 acetylation and induced indoleamine-2,3-dioxygenase. Our data demonstrate that HDAC inhibition reduces inflammatory responses of PBMC but enhances Tregs after allo-HCT.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Adult
  • Aged
  • Cytokines / antagonists & inhibitors
  • Cytokines / biosynthesis
  • Female
  • Forkhead Transcription Factors
  • Gene Expression Regulation
  • Graft vs Host Disease / prevention & control*
  • Hematopoietic Stem Cell Transplantation*
  • Histone Deacetylase Inhibitors / therapeutic use*
  • Histone Deacetylases / genetics*
  • Histone Deacetylases / metabolism
  • Histones / genetics
  • Histones / immunology
  • Humans
  • Hydroxamic Acids / therapeutic use*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / immunology
  • Inflammation / drug therapy
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / pathology
  • Leukocyte Common Antigens
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / pathology
  • Lymphocyte Count
  • Male
  • Middle Aged
  • Platelet Endothelial Cell Adhesion Molecule-1
  • STAT3 Transcription Factor / agonists
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / immunology
  • Signal Transduction
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / pathology
  • Toll-Like Receptor 4
  • Transplantation, Homologous
  • Vorinostat

Substances

  • Cytokines
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Platelet Endothelial Cell Adhesion Molecule-1
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Vorinostat
  • Leukocyte Common Antigens
  • Histone Deacetylases