T‐helper cell‐mediated factors in drug‐induced liver injury

Wang, Xinzhi; Zhang, Luyong; Jiang, Zhenzhou

doi:10.1002/jat.3115

Cited by 12 publications

(11 citation statements)

References 62 publications

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“…A similar profile of antigen-specific and unspecific stimulation was observed in patients with HEV-induced AH and ALF[59] and in chronic hepatitis B infection after anti-CD3/CD28 (unspecific) stimulation[56]. Our results did not confirm the TReg influence in non-viral ALF patients, which corroborates other results[61-63]. The expansion of T helper cells (Th17) and the suppression TReg cell production are involved in the mechanisms of liver damage in drug-induced liver disease[61,63].…”

Section: Discussionsupporting

confidence: 86%

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Changes in cellular proliferation and plasma products are associated with liver failure

Melgaço¹,

Soriani²,

Sucupira³

et al. 2016

WJH

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AIMTo study the differences in immune response and cytokine profile between acute liver failure and self-limited acute hepatitis.METHODSForty-six patients with self-limited acute hepatitis (AH), sixteen patients with acute liver failure (ALF), and twenty-two healthy subjects were involved in this study. The inflammatory and anti-inflammatory products in plasma samples were quantified using commercial enzyme-linked immunoassays and quantitative real-time PCR. The cellular immune responses were measured by proliferation assay using flow cytometry. The groups were divided into viral- and non-viral-induced self-limited AH and ALF. Thus, we worked with five groups: Hepatitis A virus (HAV)-induced self-limited acute hepatitis (HAV-AH), HAV-induced ALF (HAV-ALF), non-viral-induced self-limited acute hepatitis (non-viral AH), non-viral-induced acute liver failure (non-viral ALF), and healthy subjects (HC). Comparisons among HAV and non-viral-induced AH and ALF were performed.RESULTSThe levels of mitochondrial DNA (mtDNA) and the cytokines investigated [interleukin (IL)-6, IL-8, IL-10, interferon gamma, and tumor necrosis factor] were significantly increased in ALF patients, independently of etiology (P < 0.05). High plasma mtDNA and IL-10 were the best markers associated with ALF [mtDNA: OR = 320.5 (95%CI: 14.42-7123.33), P < 0.0001; and IL-10: OR = 18.8 (95%CI: 1.38-257.94), P = 0.028] and death [mtDNA: OR = 12.1 (95%CI: 2.57-57.07), P = 0.002; and IL-10: OR = 8.01 (95%CI: 1.26-50.97), P = 0.027]. In the cellular proliferation assay, NKbright, NKT and regulatory T cells (TReg) predominated in virus-specific stimulation in HAV-induced ALF patients with an anergic behavior in the cellular response to mitotic stimulation. Therefore, in non-viral-induced ALF, anergic behavior of activated T cells was not observed after mitotic stimulation, as expected and as described by the literature.CONCLUSIONmtDNA and IL-10 may be predictors of ALF and death. TReg cells are involved in immunological disturbance in HAV-induced ALF.

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Section: Discussionsupporting

confidence: 86%

“…Our results did not confirm the TReg influence in non-viral ALF patients, which corroborates other results[61-63]. The expansion of T helper cells (Th17) and the suppression TReg cell production are involved in the mechanisms of liver damage in drug-induced liver disease[61,63]. …”

Section: Discussionsupporting

confidence: 56%

Changes in cellular proliferation and plasma products are associated with liver failure

Melgaço¹,

Soriani²,

Sucupira³

et al. 2016

WJH

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“…There is growing evidence that immune and inflammatory responses are associated with the pathogenesis of DILI. 39 In this study, however, mRNA expression levels of most inflammation-related factors and immune-related transcription factors did not increase in the DEX/BSO/ELP group (Figure 3a and b). This result is probably due to the antiinflammatory and immunosuppressive effects of DEX.…”

Section: Discussioncontrasting

confidence: 54%

Establishment of a mouse model of enalapril-induced liver injury and investigation of the pathogenesis

Shirai

Oda

Makino

et al. 2017

Laboratory Investigation

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Drug-induced liver injury (DILI) is a major concern in drug development and clinical drug therapy. Since the underlying mechanisms of DILI have not been fully understood in most cases, elucidation of the hepatotoxic mechanisms of drugs is expected. Although enalapril (ELP), an angiotensin-converting enzyme inhibitor, has been reported to cause liver injuries with a low incidence in humans, the precise mechanisms by which ELP causes liver injury remains unknown. In this study, we established a mouse model of ELP-induced liver injury and analyzed the mechanisms of its hepatotoxicity. Mice that were administered ELP alone did not develop liver injury, and mice that were pretreated with a synthetic glucocorticoid dexamethasone (DEX) and a glutathione synthesis inhibitor l-buthionine-(S,R)-sulfoximine (BSO) exhibited liver steatosis without significant increase in plasma alanine aminotransferase (ALT). In mice pretreated with DEX and BSO, ALT levels were significantly increased after ELP administration, suggesting that hepatic steatosis sensitized the liver to ELP hepatotoxicity. An immunohistochemical analysis showed that the numbers of myeloperoxidase-positive cells that infiltrated the liver were significantly increased in the mice administered DEX/BSO/ELP. The levels of oxidative stress-related factors, including hepatic heme oxygenase-1, serum hydrogen peroxide and hepatic malondialdehyde, were elevated in the mice administered DEX/BSO/ELP. The involvement of oxidative stress in ELP-induced liver injury was further supported by the observation that tempol, an antioxidant agent, ameliorated ELP-induced liver injury. In conclusion, we successfully established a model of ELP-induced liver injury in DEX-treated steatotic mice and demonstrated that oxidative stress and neutrophil infiltration are involved in the pathogenesis of ELP-induced liver injury.

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“…However, the continued actions of these cells in liver tissue can cause damage and autoimmune reactions, especially in the context of chronic viral infection. Therefore, many regulatory mechanisms of the immune system control specific immune responses against viruses to avoid these problems ( 7 – 9 ). The liver itself, which is constantly exposed to antigenic stimulation, has acquired specialized mechanisms and cells that mediate immunotolerance properties and prevent excessive activation of the immune response ( 10 – 12 ).…”

Section: Introductionmentioning

confidence: 99%

The −3279C>A and −924A>G polymorphisms in the FOXP3 Gene Are Associated With Viral Load and Liver Enzyme Levels in Patients With Chronic Viral Liver Diseases

et al. 2018

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The transcription factor FOXP3 is an essential marker of the development and activation of regulatory T cells (Tregs), which are cells specialized in the regulation and normal tolerance of the immune response. In the context of chronic viral liver diseases, Tregs participate in the maintenance of infections by promoting histopathological control and favor the immune escape of viral agents by suppressing the antiviral response. Single nucleotide polymorphisms (SNPs) may influence the function of FOXP3 in a number of pathological conditions. The present study sought to evaluate the influence of SNPs in the FOXP3 gene promoter region in patients with chronic viral liver diseases. Three SNPs (−3279C>A, −2383C>T, and −924A>G) were analyzed in groups of patients with chronic hepatitis C (CHC), active chronic hepatitis B (CHB-A), inactive chronic hepatitis B (CHB-I), and a healthy control group (CG) using real-time PCR. The frequencies of the polymorphic variants were compared between groups and correlated with liver histopathological characteristics and enzyme levels [i.e., alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT)] obtained via biopsy and from the clinical records of the participating patients, respectively. For the −2338C>T SNP, no significant differences were found in the frequencies of variants between groups or in the histological findings. Significant associations between the polymorphisms and the CHB-I group were not established. The −3279C>A SNP was associated with altered viral loads (log10) and GGT levels in CHC patients with advanced stages of inflammatory activity and liver fibrosis. The −924A>G SNP was associated with altered viral loads (log10) and liver enzyme levels among CHB-A patients with milder inflammation and fibrosis. However, the frequencies of the −3279C>A and −924A>G polymorphisms were not directly associated with the histopathological profiles of the analyzed patients. These polymorphic variants may influence hepatic function in patients with chronic viral liver diseases but are not directly associated with the establishment of the degree of inflammatory activity and liver fibrosis.

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T‐helper cell‐mediated factors in drug‐induced liver injury

Cited by 12 publications

References 62 publications

Changes in cellular proliferation and plasma products are associated with liver failure

Changes in cellular proliferation and plasma products are associated with liver failure

Establishment of a mouse model of enalapril-induced liver injury and investigation of the pathogenesis

The −3279C>A and −924A>G polymorphisms in the FOXP3 Gene Are Associated With Viral Load and Liver Enzyme Levels in Patients With Chronic Viral Liver Diseases

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