Differential profile of activated regulatory T cell subsets and microRNAs in tolerant liver transplant recipients

Revilla-Nuin, Beatriz; Bejar, África de; Martı́nez-Alarcón, L.; Herrero, J.I.; Martínez-Cáceres, Carlos Manuel; Ramı́rez, Pablo; Baroja‐Mazo, Alberto; Pons, J.A.

doi:10.1002/lt.24691

Cited by 23 publications

(25 citation statements)

References 37 publications

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“…MiRNAs can target mRNAs that regulate production of the DNA methyltransferases, and failures in enzyme production can limit DNA methylation and alter gene activity . Cytokine pathways that direct the differentiation and proliferation of lymphocytes are regulated in part by the miRNAs and homeostatic mechanisms that suppress immune reactivity and tumour formation may also be affected by these gene‐silencing molecules (Table ).…”

Section: Resultsmentioning

confidence: 99%

“…Histone modifications are influenced by enzymes including the histone deacetylases (HDCAs), histone acetyltransferases (HATs), histone methyltransferases (HMTs), histone demethylases and the PAD enzyme family [69,83,[85][86][87][88]. MiRNAs can be manipulated by antisense oligonucleotides that inactivate mRNA before translation to miRNAs [226,227] and by epigenetic modifications of methylation-sensitive genes that express the miRNAs [109,110,131,132]. All elements have been manipulated in experimental models of immune-mediated and malignant diseases [33,43,70,126,228,229].…”

Section: Key Elementsmentioning

confidence: 99%

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Epigenetic changes and their implications in autoimmune hepatitis

Czaja

2018

Eur J Clin Investigation

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Background: The genetic risk of autoimmune hepatitis is insufficient to explain the observed risk, and epigenetic changes may explain disparities in disease occurrence in different populations within and between countries. The goal of this review was to examine how epigenetic changes induced by the environment or inherited as a phenotypic trait may affect autoimmune hepatitis and be amenable to therapeutic intervention. Materials and methods: Pertinent abstracts were identified in PubMed by multiple search terms. The number of abstracts reviewed was 1689, and the number of full-length articles reviewed exceeded 150. Results: Activation of pro-inflammatory genes in autoimmune disease is associated with hypomethylation of deoxyribonucleic acid and modification of histones within chromatin. Organ-specific microribonucleic acids can silence genes by marking messenger ribonucleic acids for degradation, and they can promote inflammatory activity or immunosuppression. High circulating levels of the microribonucleic acids 21 and 122 have been demonstrated in autoimmune hepatitis, and they may increase production of pro-inflammatory cytokines. Microribonucleic acids are also essential for maintaining regulatory T cells. Drugs, pollutants, infections, diet and ageing can induce inheritable epigenetic changes favouring autoimmunity. Reversal is feasible by manipulating enzymes, transcription factors, gene-silencing molecules and toxic exposures or by administering methyl donors and correcting vitamin D deficiency. Gene targets, site specificity, efficacy and consequences are uncertain. Conclusions: Potentially reversible epigenetic changes may affect the occurrence and outcome of autoimmune hepatitis, and investigations are warranted to determine the nature of these changes, key genomic targets, and feasible interventions and their consequences.

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Section: Resultsmentioning

confidence: 99%

Section: Key Elementsmentioning

confidence: 99%

Epigenetic changes and their implications in autoimmune hepatitis

Czaja

2018

Eur J Clin Investigation

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“…Hence, the plasma levels of miR-155-5p and miR-181a-5p after LT potentially help identify patients for IS minimization. Revilla-Nuin et al have reported a set of differentially expressed miRNAs in tolerant recipients after liver transplantation that might promote and control the activation of Tregs necessary to develop operational tolerance (141). Their study showed that miR95, miR24, miR31, miR146a, and miR155 were expressed more in tolerant than in non-tolerant recipients, and were positively correlated with activated Treg markers.…”

Section: Mirnas As Biomarkersmentioning

confidence: 99%

Strategies for Deliberate Induction of Immune Tolerance in Liver Transplantation: From Preclinical Models to Clinical Application

et al. 2020

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The liver exhibits intrinsic immune regulatory properties that maintain tolerance to endogenous and exogenous antigens, and provide protection against pathogens. Such an immune privilege contributes to susceptibility to spontaneous acceptance despite major histocompatibility complex mismatch when transplanted in animal models. Furthermore, the presence of a liver allograft can suppress the rejection of other solid tissue/organ grafts from the same donor. Despite this immune privilege of the livers, to control the undesired alloimmune responses in humans, most liver transplant recipients require long-term treatment with immune-suppressive drugs that predispose to cardiometabolic side effects and renal insufficiency. Understanding the mechanism of liver transplant tolerance and crosstalk between a variety of hepatic immune cells, such as dendritic cells, Kupffer cells, liver sinusoidas endothelial cells, hepatic stellate cells and so on, and alloreactive T cells would lead to the development of strategies for deliberate induction of more specific immune tolerance in a clinical setting. In this review article, we focus on results derived from basic studies that have attempted to elucidate the immune modulatory mechanisms of liver constituent cells and clinical trials that induced immune tolerance after liver transplantation by utilizing the immune-privilege potential of the liver.

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“…These 2 issues are linked by Revilla‐Nuin et al in this issue . Using a cohort of liver transplant recipients who had previously been enrolled in immunosuppression withdrawal trials, the authors compared blood samples from patients who had experienced rejection during withdrawal and had thus been restarted on baseline immunosuppression nontolerant (non‐Tol) compared with those who had been successfully weaned from immunosuppression tolerant (Tol) without experiencing rejection for more than 1 year after withdrawal.…”

mentioning

confidence: 99%

“…Without FOXP3 staining or Treg‐suppressive functional testing, these cells must be viewed as a somewhat mixed T cell population . This perspective is key to interpreting the 3 main results of this study that compared Tregs and microRNAs (miRNAs) in 24 Tol and 23 non‐Tol liver transplant recipients …”

mentioning

confidence: 99%