Histone deacetylase inhibition alters dendritic cells to assume a tolerogenic phenotype and ameliorates arthritis in SKG mice

Koyama, Misaki; Morinobu, Akio; Saegusa, Jun; Kasagi, Shimpei; Fujita, Masaaki; Miyamoto, Yukio; Matsuki, Fumichika; Kumagai, Shunichi

doi:10.1186/ar3339

Cited by 23 publications

(22 citation statements)

References 52 publications

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“…However the results also suggest that dendritic cells may become more tolerogenic in the presence of TSA, since the number of Tregs generated in the presence of TSA and dendritic cells needed to achieve 50% suppression is half of those generated in the presence of activating antibodies (ratio 1 : 0.5 in the presence of dendritic cells versus 1 : 1 in the presence of activating antibodies). Consistently, it has been reported that TSA can change dendritic cells into a tolerogenic phenotype in vitro [19], so the evidence points to the fact that both Tregs and dendritic cells are targets for TSA.…”

Section: Discussionsupporting

confidence: 53%

Trichostatin A Promotes the Generation and Suppressive Functions of Regulatory T Cells

Doñas

Fritz

Manrı́quez

et al. 2013

Clinical and Developmental Immunology

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Regulatory T cells are a specific subset of lymphocytes that suppress immune responses and play a crucial role in the maintenance of self-tolerance. They can be generated in the thymus as well as in the periphery through differentiation of naïve CD4+ T cells. The forkhead box P3 transcription factor (Foxp3) is a crucial molecule regulating the generation and function of Tregs. Here we show that the foxp3 gene promoter becomes hyperacetylated in in vitro differentiated Tregs compared to naïve CD4+ T cells. We also show that the histone deacetylase inhibitor TSA stimulated the in vitro differentiation of naïve CD4+ T cells into Tregs and that this induction was accompanied by a global increase in histone H3 acetylation. Importantly, we also demonstrated that Tregs generated in the presence of TSA have phenotypical and functional differences from the Tregs generated in the absence of TSA. Thus, TSA-generated Tregs showed increased suppressive activities, which could potentially be explained by a mechanism involving the ectonucleotidases CD39 and CD73. Our data show that TSA could potentially be used to enhance the differentiation and suppressive function of CD4+Foxp3+ Treg cells.

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Section: Discussionsupporting

confidence: 53%

Trichostatin A Promotes the Generation and Suppressive Functions of Regulatory T Cells

Doñas

Fritz

Manrı́quez

et al. 2013

Clinical and Developmental Immunology

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“…This is in accordance with previously published reports on the ability of HDAi to induce IDO in DC, thus protecting mice from GVHD lethality [109]. In addition, TSA inhibited the zymosan-induced T-cell stimulatory ability of BM DC and skewed DC function toward a tolerogenic phenotype [108]. Although this study failed to examine IDO function after DC treatment with TSA and zymosan, it is possible that the up-regulation of both IDO1 and IDO2 play a role in the amelioration of chronic arthritis through the inhibition of DC function.…”

Section: Animal Models Of Rasupporting

confidence: 92%

“…Mice were treated with TSA from day 14 (before the onset of arthritis) through day 22 (after the onset of arthritis). TSA prevented the development of arthritis, as shown by the histological arthritis scores [108]. IL-17 production by lymph node cells was dramatically reduced in TSA-treated mice, which was paralleled by an increase of Treg cells.…”

Section: Animal Models Of Ramentioning

confidence: 95%

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Emerging Concepts on Inhibitors of Indoleamine 2,3-Dioxygenase in Rheumatic Diseases

Filippini

Papa

Sambataro

et al. 2012

CMC

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The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) finely regulates both innate and adaptive immune responses through the degradation of the essential amino acid tryptophan into kynurenine and other downstream metabolites, which suppress effector T-cell function and promote the differentiation of regulatory T cells. A novel role for IDO1 as a signaling molecule and a modifier of innate inflammatory responses is now emerging. In particular, IDO1 can either support or antagonize inflammation in a context- and tissuedependent manner. Studies in experimental arthritis have unravelled a previously unappreciated role for IDO in controlling B-cell activation and autoantibody production. IDO dysregulation has been documented in patients with systemic lupus erythematosus, systemic sclerosis and Sjogren's syndrome, as well as in severe sepsis and chronic kidney disease. This article summarizes the contribution of IDO to the pathophysiology of inflammatory/autoimmune disorders, and discusses whether strategies to restore metabolic equilibrium in the kynurenine pathway might be pursued in diseases states such as rheumatoid arthritis and systemic sclerosis.

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“…Our data revealed that tumor-induced polarization of immunostimulatory cDCs into immunosuppressive regDCs in vitro was also accompanied by fast activation of STAT3 in treated cells (Shurin, unpublished data). Interestingly, histone deacetylase inhibition has been also reported to alter DCs to assume a tolerogenic phenotype [121]. Recently, Sun et al demonstrated that histone deacetylase inhibition acetylates and activates STAT-3, which regulates DCs by promoting the transcription of IDO.…”

Section: Regulatory Dendritic Cells: Initiating Signaling Pathwaysmentioning

confidence: 99%

Tumor associated regulatory dendritic cells

Shurin

Gutkin

2012

Seminars in Cancer Biology

114

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Immune effector and regulatory cells in the tumor microenvironment are key factors in tumor development and progression as the pathogenesis of cancer vitally depends on the multifaceted interactions between various microenvironmental stimuli provided by tumor-associated immune cells. Immune regulatory cells participate in all stages of cancer development from the induction of genomic instability to the maintenance of intratumoral angiogenesis, proliferation and spreading of malignant cells, and formation of premetastatic niches in distal tissues. Dendritic cells in the tumor microenvironment serve as a double-edged sword and, in addition to initiating potent anti-tumor immune responses, may mediate genomic damage, support neovascularization, block anti-tumor immunity and stimulate cancerous cell growth and spreading. Regulatory dendritic cells in cancer may directly and indirectly maintain antigen-specific and non-specific T cell unresponsiveness by controlling T cell polarization, MDSC and Treg differentiation and activity, and affecting specific microenvironmental conditions in premalignant niches. Understanding the mechanisms involved in regulatory dendritic cell polarization and operation and revealing pharmacological means for harnessing these pathways will provide additional opportunities for modifying the tumor microenvironment and improving the efficacy of different therapeutic approaches to cancer.

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Histone deacetylase inhibition alters dendritic cells to assume a tolerogenic phenotype and ameliorates arthritis in SKG mice

Cited by 23 publications

References 52 publications

Trichostatin A Promotes the Generation and Suppressive Functions of Regulatory T Cells

Trichostatin A Promotes the Generation and Suppressive Functions of Regulatory T Cells

Emerging Concepts on Inhibitors of Indoleamine 2,3-Dioxygenase in Rheumatic Diseases

Tumor associated regulatory dendritic cells

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