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

Sung Won Choi, Erin Gatza, Guoqing Hou, Yaping Sun, Joel Whitfield, Yeohan Song, Katherine Oravecz-Wilson, Isao Tawara, Charles A. Dinarello and Pavan Reddy

Key points

  • HDAC inhibition reduced pro-inflammatory cytokines and increased regulatory T cell number and function after allo-HCT.

  • HDAC inhibition enhanced STAT-3 acetylation and induced IDO after allo-HCT.

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.

  • Submitted October 8, 2014.
  • Accepted November 20, 2014.