Histone/protein deacetylase inhibitors increase suppressive functions of human FOXP3+ Tregs

Akimova, Tatiana; Ge, Guanghui; Golovina, Tatiana; Mikheeva, Tatiana; Wang, Liqing; Riley, James L.; Hancock, Wayne W.

doi:10.1016/j.clim.2010.04.018

Cited by 115 publications

(117 citation statements)

References 56 publications

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“…48 Although many HDAC remain to be evaluated, the available data emphasize the value of targeting particular class II or class III enzymes, whereas our pharmacologic targeting of class I HDAC had no obvious effects on murine Treg function in vitro or in vivo. 49 However, this contrasts with our own 37 and other data 38 using human cells, as well as with data from rat models. 50,51 Several explanations may apply.…”

Section: Hdaci and Tregscontrasting

confidence: 53%

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Histone/protein deacetylases and T-cell immune responses

Akimova¹,

Beier

Liu³

et al. 2012

Blood

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124

100

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Clinical and experimental studies show that inhibition of histone/protein deacetylases (HDAC) can have important antineoplastic effects through cytotoxic and proapoptotic mechanisms. There are also increasing data from nononcologic settings that HDAC inhibitors (HDACi) can exhibit useful anti-inflammatory effects in vitro and in vivo, unrelated to cytotoxicity or apoptosis. These effects can be cell-, IntroductionHistone/protein deacetylase inhibitors (HDACi) were initially developed as anti-cancer agents, and much clinical and molecular data regarding their effects arose in the oncology field. However, nowadays HDACi are attracting interest as anti-inflammatory agents, independent of their known proapoptotic or cell cycle arrest actions on malignant cells. Although pan-HDACi enzymes have the potential to modulate the functions of all cells, their effects on T cells, and on CD4 ϩ FOXP3 ϩ T-regulatory (Treg) cells in particular, are of interest given the burgeoning role for Tregs in the area of cellular therapy. Treg-based therapies, involving ex vivo expansion and adoptive transfer to boost circulating Treg numbers, are proposed as therapies of neurodegenerative and autoimmune diseases, as well as GVHD and organ transplant rejection. 1 However, in inflammatory conditions, conventional T cells can be resistant to suppression by Tregs, 2 and pro-inflammatory cytokines (TNF-␣, IL-1, IL-6, IFN-␥), lipopolysaccharides, and other agents have deleterious effects on Tregs, impairing their suppressive phenotype 3 and promoting their conversion into Th17 4 or Th1 5 cells. 6,7 Moreover, the extent to which patients with autoimmune diseases have decreased numbers of Treg cells remains unclear. 8 An alternate therapeutic strategy to transfer of Treg cells is to use pharmacologic agents, such as rapamycin 9 or HDACi, to curtail T-cell responses and facilitate Treg functions. We have shown that HDACi can enhance Treg suppressive function and promote their development in vitro and in vivo, 10 with beneficial actions for transplantation 11 and autoimmune diseases, including colitis 12,13 and arthritis. 14 This review summarizes some of the background and promise of HDACi therapy to modulate T cell-associated inflammatory and immunologic diseases. We apologize to those researchers whose work could not be cited because of limited space. HDAC and HDACiHistone/protein deacetylases (HDAC) remove acetyl groups (O ϭ C-CH3) from ⑀-N-acetyl lysine amino acids and are classified into 4 main classes of enzymes [15][16][17] : class I HDAC include HDAC1, 2, 3, and 8; class II HDAC include HDAC4, 5, 7, 9 (subclass IIa) and HDAC 6, 10 (subclass IIb); class III HDAC are homologs of yeast Sir2 proteins; and the sole class IV HDAC is HDAC11.Class I HDAC enzymes are expressed in all cells, whereas class IIa HDAC enzymes have tissue-specific expression. Historically, class I HDAC were thought largely restricted to the nucleus, whereas class IIa HDAC enzymes shuttled between the nucleus and cytoplasm 15,16 and even mitochondria (HDAC7). 18 How...

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Section: Hdaci and Tregscontrasting

confidence: 53%

“…11 Pan-HDACi use also enhances the suppressive function of human Tregs in vitro 37 and promotes conversion of human T cells into suppressive Tregs. 38 The transcription factor, Foxp3, has an indispensable role in Treg biology 39 and is subject to epigenetic modifications that regulate its gene expression and protein function.…”

Section: Hdaci and Tregsmentioning

confidence: 99%

Histone/protein deacetylases and T-cell immune responses

Akimova¹,

Beier

Liu³

et al. 2012

Blood

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124

100

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“…by guest www.bloodjournal.org From increased Treg numbers and enhanced their suppressive function but did not directly alter non-Treg, that is, Tconv, responses. 3,6,14,20 HDAC inhibition can also enhance suppression by human Tregs 21 and promote the conversion of human T cells into Tregs in vitro. 22 We therefore explored the effect of HDAC inhibition with vorinostat on both Tregs and Tconv after clinical allogeneic BMT.…”

Section: Resultsmentioning

confidence: 99%

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

Choi

Gatza

Hou

et al. 2015

Blood

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Key Points• HDAC inhibition reduced proinflammatory cytokines and increased regulatory T-cell number and function after allo-HCT.• HDAC inhibition enhanced signal transducer and activator of transcription 3 acetylation and induced indoleamine-2,3-dioxygenase after allo-HCT.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. (Blood. 2015;125(5):815-819)

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“…Of note, these effects are confirmed in vivo by showing that TSA promotes Treg-dependent permanent cardiac and islet allograft survival (41). Further evidence indicates that functional enhancement also is prompted in freshly isolated and expanded human Treg by several HDACi with different molecular moieties (42). Apparently, promotion of Treg functions by HDACi is due to increased expression of the negative immune regulator CTLA-4 (CD152) (42).…”

Section: Possible Mechanisms Underlying the Therapeutic Effects Of Hdmentioning

confidence: 52%

“…Further evidence indicates that functional enhancement also is prompted in freshly isolated and expanded human Treg by several HDACi with different molecular moieties (42). Apparently, promotion of Treg functions by HDACi is due to increased expression of the negative immune regulator CTLA-4 (CD152) (42). Overall, these findings suggest that the neuroprotective effects of HDACi in mice with EAE might be due, at least in part, to increased immune suppressing activities of Treg.…”

Section: Possible Mechanisms Underlying the Therapeutic Effects Of Hdmentioning

confidence: 68%

The Therapeutic Potential of HDAC Inhibitors in the Treatment of Multiple Sclerosis

Faraco

Cavone

Chiarugi

2011

Mol Med

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Multiple sclerosis (MS) is a devastating autoimmune disorder of the central nervous system (CNS) for which there is no efficacious cure. Thanks to numerous preclinical and clinical studies, drugs able to mitigate the inexorable course of the disease have been made available recently. Still, there is a terrible need for compounds capable of reducing the severity of the autoimmune attack and of blocking progression of the disorder. Also, besides the classic immunosuppressive strategies, it is now appreciated that compounds directly targeting neuronal death can be of relevance to the treatment of MS patients. Acetylation homeostasis is a key regulator of both immune cell activation and neuronal survival. Of note, potent histone deacetylase inhibitors (HDACi) endowed with antiinflammatory and neuroprotective properties have been identified. Efficacy of HDACi in experimental models of MS has been reported consistently. In this review, we provide an appraisal of the literature on HDACi and MS, also discussing the mechanisms by which HDACi can suppress the autoimmune attack to the CNS.

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Histone/protein deacetylase inhibitors increase suppressive functions of human FOXP3+ Tregs

Cited by 115 publications

References 56 publications

Histone/protein deacetylases and T-cell immune responses

Histone/protein deacetylases and T-cell immune responses

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

The Therapeutic Potential of HDAC Inhibitors in the Treatment of Multiple Sclerosis

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