Valproic Acid Ameliorates Graft-versus-Host Disease by Downregulating Th1 and Th17 Cells

Long, Jun; Chang, Li; Shen, Yan; Gao, Wenhui; Wu, Yan; Dou, Han-bo; Huang, Mengmeng; Wang, Ying; Fang, Weiyue; Shan, Jiehui; Wang, Yueying; Zhu, Jiang; Zhu, Chen; Hu, Jiong

doi:10.4049/jimmunol.1500578

Cited by 24 publications

(15 citation statements)

References 58 publications

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“…Recent reports with VPA have suggested its use in a variety of field from immunomodulation to cancer therapy; it is also being tested in clinics for epileptic therapy (Krauze et al ., ; Long et al ., ; Yves et al ., ). It is widely used in therapy as an anticonvulsive agent; is an HDAC inhibitor which is known to inhibit cell proliferation and initiate differentiation.…”

Section: Resultsmentioning

confidence: 99%

Valproic acid enhances the neural differentiation of human placenta derived-mesenchymal stem cellsin vitro

Talwadekar

Fernandes

Kale

et al. 2016

J Tissue Eng Regen Med

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Mesenchymal stem cells (MSCs) are known to express a wide range of markers belonging to all the three lineages: mesodermal, ectodermal and endodermal. Therefore, the possibility of their transdifferentiation towards a neural lineage has been an aspect of active research. In the present study, MSCs were isolated from human placental tissue (P-MSC) and subjected them to neural differentiation. It was found that the P-MSCs differentiated towards neural lineage in appropriate differentiation conditions. However, when a histone deacetylase (HDAC) inhibitor - valproic acid (VPA) - was incorporated in the medium, there was a further increase in their neural differentiation potential. The increase in the number of neurites and neural lineage specific markers was notable. The VPA-treated cells showed a significantly elevated membrane potential compared with the cells grown in only differentiation medium. When the molecular mechanism was studied, the enhancement in the neuronal lineage specification was caused by the inhibition of bone morphogenetic protein (BMP) 2 and an increase in BMP4 under both conditions. The target of VPA (HDAC2) was reduced in the VPA set, whereas HDAC1 remained unchanged. Concurrent reduction in the levels of Stat3 was observed, leading to an upregulation of βIII tubulin, which is a neuronal lineage-specific marker. The components of Notch signalling (i.e. decreased notch 1 and increased notch 3) also supported differentiation towards the neuronal lineage. Thus, the VPA treated P-MSCs can serve as an alternative source for deriving neural cells for use in both research and in clinics. Copyright © 2016 John Wiley & Sons, Ltd.

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Section: Resultsmentioning

confidence: 99%

Valproic acid enhances the neural differentiation of human placenta derived-mesenchymal stem cellsin vitro

Talwadekar

Fernandes

Kale

et al. 2016

J Tissue Eng Regen Med

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“…9, 30 The results of both of those earlier studies 9,30 suggested that downregulating Th1 and Th17 cells could ameliorate GVHD.…”

Section: Discussionmentioning

confidence: 96%

Regulatory B cells promote graft-versus-host disease prevention and maintain graft-versus-leukemia activity following allogeneic bone marrow transplantation

Zhao

et al. 2017

OncoImmunology

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Regulatory B cells (Bregs) are involved in the pathogenesis of graft-versus-host disease (GVHD). However, whether Bregs can alleviate acute GVHD without compromising graft-versus-leukemia (GVL) effects remains unclear. Here, we evaluated the role of Bregs in acute GVHD and GVL activity in both a mouse model and a clinical cohort study. In the acute GVHD mouse model, co-transplantation of Bregs prevents onset through inhibiting Th1 and Th17 differentiation and expanding regulatory T cells. In the GVL mouse model, Bregs contributed to the suppression of acute GVHD but had no adverse effect on GVL activity. In the clinical cohort study, a higher dose of Bregs in allografts was associated with a lower cumulative incidence of acute GVHD but not with increased risk of relapse. Our data demonstrate that Bregs can prevent acute GVHD and maintain GVL effects and suggest that Bregs have potential as a novel strategy for acute GVHD alleviation.

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“…Our results suggest that VPA could be used to target NK cells in pathological injury. In fact, VPA has shown promising effects in down-modulating inflammation in different pathological models such as during intestinal injury, autoimmune encephalomyelitis and acute allograft rejection 14,59,60 . Interestingly, NK cells are associated with a number of inflammatory pathologies such as type1 diabetes 61 , psoriasis 62 , lichen planus 63 , rheumatoid arthritis 64 , periodontal disease 65 , chronic obstructive pulmonary disease 66 , atherosclerosis 67 , among others.…”

Section: Discussionmentioning

confidence: 99%

Valproic acid inhibits interferon-γ production by NK cells and increases susceptibility to Listeria monocytogenes infection

Soria-Castro

Chávez‐Blanco

Garcı́a-Pérez

et al. 2020

Sci Rep

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Valproic acid (VPA) is a drug commonly used for epileptic seizure control. Recently, it has been shown that VPA alters the activation of several immune cells, including Natural Killer (NK) cells, which play an important role in the containment of viruses and intracellular bacteria. Although VPA can increase susceptibility to extracellular pathogens, it is unknown whether the suppressor effect of VPA could affect the course of intracellular bacterial infection. This study aimed to evaluate the role of VPA during Listeria monocytogenes (L.m) infection, and whether NK cell activation was affected. We found that VPA significantly augmented mortality in L.m infected mice. This effect was associated with increased bacterial load in the spleen, liver, and blood. Concurrently, decreased levels of IFN-γ in serum and lower splenic indexes were observed. Moreover, in vitro analysis showed that VPA treatment decreased the frequency of IFN-γ-producing NK cells within L.m infected splenocytes. Similarly, VPA inhibited the production of IFN-γ by NK cells stimulated with IL-12 and IL-18, which is a crucial system for early IFN-γ production in listeriosis. Finally, VPA decreased the phosphorylation of STAT4, p65, and p38, without affecting the expression of IL-12 and IL-18 receptors. Altogether, our results indicate that VPA increases the susceptibility to Listeria monocytogenes infection and suggest that NK cell is one of the main targets of VPA, but further work is needed to ascertain this effect.

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Valproic Acid Ameliorates Graft-versus-Host Disease by Downregulating Th1 and Th17 Cells

Cited by 24 publications

References 58 publications

Valproic acid enhances the neural differentiation of human placenta derived-mesenchymal stem cellsin vitro

Valproic acid enhances the neural differentiation of human placenta derived-mesenchymal stem cellsin vitro

Regulatory B cells promote graft-versus-host disease prevention and maintain graft-versus-leukemia activity following allogeneic bone marrow transplantation

Valproic acid inhibits interferon-γ production by NK cells and increases susceptibility to Listeria monocytogenes infection

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