Decitabine induces regulatory T cells, inhibits the production of IFN-gamma and IL-17 and exerts preventive and therapeutic efficacy in rodent experimental autoimmune neuritis

Fagone, Paolo; Mazzon, Emanuela; Chikovani, Tinatin; Saraceno, Andrea; Mammana, Santa; Colletti, Giuseppe; Mangano, Katia; Bramantı, Placido; Nicoletti, Ferdinando

doi:10.1016/j.jneuroim.2018.05.013

Cited by 18 publications

(11 citation statements)

References 47 publications

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“…It should however be noticed that, regardless of the specific anti-arthritogenic pathways affected by DAC, the efficacy has been short lasting, as treatment interruption was associated with recurrence and/or exacerbation of type II CIA. This is consistent with our previous observation in EAE [26] and EAN [27], and indicates that prolonged treatment with DAC may be needed if these findings will be translated into the clinical setting.…”

Section: Discussionsupporting

confidence: 92%

“…We have not presently investigated whether, as in type 1 diabetes in Non-obese diabetic (NOD) mice [23] and rodent EAE [24][25][26] and experimental autoimmune neuritis (EAN) [27], DAC also increased the frequency and/or the function of regulatory T cells. This is likely to have occurred, as it is a known demonstrated immunopharmacological mode of action of DAC and, if so, this may have further contributed to the beneficial effects of DAC.…”

Section: Discussionmentioning

confidence: 99%

“…As an inhibitor of DNA methyltransferases (DNMTs), it induces demethylation and reactivation of silenced genes [22]. Previous studies by ourselves and others have shown that treatment with DAC ameliorates the course of rodent models of autoimmune diseases, such as type 1 diabetes, MS, and Guillain Barrè syndrome (GBS), likely by inducing the upregulation of FoxP3 expression and induction of regulatory T cells [23][24][25][26][27]. In particular, independent studies have concordantly proven the beneficial effects of DAC in different rodent models of experimental autoimmune encephalomyelitis (EAE) [24][25][26], that serves as a preclinical model of MS. DAC apparently acts through an immunopharmacological mode of action that entails an increase in the number of regulatory T cells, and the reduction in the proportion of Th1 and Th17 cells [23][24][25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

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Effects of Treatment with the Hypomethylating Agent 5-aza-2′-deoxycytidine in Murine Type II Collagen-Induced Arthritis

et al. 2019

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The emerging role of epigenetics in the pathogenesis of autoimmune diseases has recently attracted much interest on the possible use of epigenetic modulators for the prevention and treatment of these diseases. In particular, we and others have shown that drugs that inhibit DNA methylation, such as azacitidine (AZA) and decitabine (DAC), already used for the treatment of acute myeloid leukemia, exert powerful beneficial effects in rodent models of type 1 diabetes, multiple sclerosis, and Guillain Barrè syndrome. Along this line of research, we have presently studied the effects of DAC in a murine model of rheumatoid arthritis induced by type II collagen and have demonstrated that DAC administration was associated with a significant amelioration of the clinical condition, along with in vivo and ex vivo modification of the immunological profile of the so-treated mice, that exhibited a diminished production of Th1 and Th17 pro-inflammatory cytokines and reduction of anti-type II collagen autoantibodies.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of Treatment with the Hypomethylating Agent 5-aza-2′-deoxycytidine in Murine Type II Collagen-Induced Arthritis

et al. 2019

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“…HDAC inhibitors have been shown to inhibit inflammatory mediator production (including cytokines, chemokines and nitric oxide) and lead to M2 polarization of macrophages (52). Moreover, experiments conducted in murine models suggest that DNMT inhibitors could be deployed in the treatment of autoimmune diseases (53,54).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic inhibitors eliminate senescent melanoma BRAFV600E cells that survive long‑term BRAF inhibition

et al. 2020

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It is estimated that ~50% of patients with melanoma harbour B-Raf (BRAF)V600 driver mutations, with the most common of these being BRAFV600E, which leads to the activation of mitogen-activated protein kinase proliferative and survival pathways. BRAF inhibitors are used extensively to treat BRAF-mutated metastatic melanoma; however, acquired resistance occurs in the majority of patients. The effects of long-term treatment with PLX4032 (BRAFV600 inhibitor) were studied in vitro on sensitive V600E BRAF-mutated melanoma cell lines. After several weeks of treatment with PLX4032, the majority of the melanoma cells died; however, a proportion of cells remained viable and quiescent, presenting senescent cancer stem cell-like characteristics. This surviving population was termed SUR cells, as discontinuing treatment allowed the population to regrow while retaining equal drug sensitivity to that of parental cells. RNA sequencing analysis revealed that SUR cells exhibit changes in the expression of 1,415 genes (P<0.05) compared with parental cells. Changes in the expression levels of a number of epigenetic regulators were also observed. These changes and the reversible nature of the senescence state were consistent with epigenetic regulation; thus, it was investigated as to whether the senescent state could be reversed by epigenetic inhibitors. It was found that both parental and SUR cells were sensitive to different histone deacetylase (HDAC) inhibitors, such as SAHA and MGCD0103, and to the cyclin-dependent kinase (CDK)9 inhibitor, CDKI-73, which induced apoptosis and reduced proliferation both in the parental and SUR populations. The results suggested that the combination of PLX4032 with HDAC and CDK9 inhibitors may achieve complete elimination of SUR cells that persist after BRAF inhibitor treatment, and reduce the development of resistance to BRAF inhibitors.

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“…In addition of being implicated in the pathogenesis of autoimmune diseases [7], such as Multiple Sclerosis [10,11,12], Guillain Barrè Syndrome [13] and Type 1 Diabetes [14], MIF has been shown to promote tumorigenesis [15] and it has been described to be overexpressed by various tumors, including mammary [16], colorectal and prostate cancer [17], melanoma [18] and glioblastoma [19,20]. Indeed, MIF may induce angiogenesis by up-regulating the secretion of vascular endothelial growth factor (VEGF) [18], may promote proliferation, by binding and deactivating JAB1, a negative regulator of p27KIP1, that in turn controls cell cycle progression at the G1 phase [21]; and may inhibit natural killer cells-mediated cytotoxicity [22].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Macrophage Migration Inhibitory Factor and Its Homologue D-Dopachrome Tautomerase as Negative Prognostic Factor in Neuroblastoma

et al. 2019

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Neuroblastoma (NB) represents one of the most frequent pediatric solid tumors. Macrophage migration inhibitory factor (MIF) is a cytokine exerting multiple biological functions. More recently, a second member of the MIF family of cytokine has been identified, the D-dopachrome tautomerase (DDT), that exerts several overlapping functions with MIF. Growing evidence suggests a key role for MIF and DDT in the development of cancer. The aim of this study is to characterize the prognostic value of MIF and DDT in NB. We show that higher expression levels of MIF and DDT in Stage 4 NB samples are associated with a poorer prognosis, independently of the presence of MYCN amplification. Moreover, higher levels of MIF are mostly enriched by Th1 cells, while lower levels of MIF are associated with an increased proportion of B cells, Cytotoxic T cells, Dendritic cells and Natural Killer T cells. We also show that treatment with the histone deacetylase (HDAC) inhibitor, vorinostat, of the NB cell line, SH-SY5Y, determines a significant reduction in the expression of both MIF and DDT. Finally, MIF and DDT inhibition by short interfering RNA is able to revert vincristine sensitivity in vitro. Overall, our data suggest that MIF exert pro-tumorigenic properties in NB, likely by dampening antigen presentation and cytotoxic immune responses, and we propose the HDAC inhibitors as a potential therapeutic strategy for NB patients.

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Decitabine induces regulatory T cells, inhibits the production of IFN-gamma and IL-17 and exerts preventive and therapeutic efficacy in rodent experimental autoimmune neuritis

Cited by 18 publications

References 47 publications

Effects of Treatment with the Hypomethylating Agent 5-aza-2′-deoxycytidine in Murine Type II Collagen-Induced Arthritis

Effects of Treatment with the Hypomethylating Agent 5-aza-2′-deoxycytidine in Murine Type II Collagen-Induced Arthritis

Epigenetic inhibitors eliminate senescent melanoma BRAFV600E cells that survive long‑term BRAF inhibition

Overexpression of Macrophage Migration Inhibitory Factor and Its Homologue D-Dopachrome Tautomerase as Negative Prognostic Factor in Neuroblastoma

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