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HDAC Inhibitors -Panobinostat - Histone deacetylase inhibition regulates inflammation and enhances Tregs after allogeneic hematopoietic cell transplantation in humans
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Blood Nov 2014
Sung Won Choi1, Erin Gatza1, Guoqing Hou1, Yaping Sun2, Joel Whitfield3, Yeohan Song1, Katherine Oravecz-Wilson2, Isao Tawara4, Charles A. Dinarello5, and Pavan Reddy2,*
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.
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.
IAS/2014: Treatment with the histone deacetylase inhibitor Panobinostat markedly reduces chronic inflammation in HIV-infected patients (07/29/14)
All these relevant inflammation studies also from IAS:
SIV-infected rhesus macaques receiving suppressive cART have continued GI damage, inflammation, immune activation and persistent low-level viral replication within lymphoid tissues"Suggesting that HIV Cure strategies will need to address sources of residual inflammation/immune activation to be successful" - (07/28/14)
Monocyte activation markers remain significantly elevated in virologically suppressed HIV+ individuals to a level equivalent to an additional 4 years of normal ageing (07/30/14)
Inflammation/Activation Markers Drop With ATV, DRV, RAL, But Not Completely - ACTG Study
ART in Acute Infection Quells Inflammation But Does Not Restore Gut CD4s - (08/11/14)
Probiotic and IL-21 Treatment Promotes Th17 Cell Recovery in ARV-Treatment of Pigtail Macaques - (08/06/14)
High Inflammation/Activation Markers Before and During ART Predict Death in MACS

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