Inhibition of the Adaptive Immune Response following Drug‐Induced Liver Injury

The aim of this study was to illustrate the initial subclinical drug-induced liver injury and the associated adaptive immune response by monitoring for the changes in plasma IL-2, IL-10, and some cytochrome P450 activity during chronic administration of nevirapine (NVP), isoniazid (INH), and paracetamol (PAR) in rats without clinical hepatotoxicity. Male Sprague-Dawley (SD) rats were divided into four groups (saline (S), NVP, INH, and PAR) of 25 animals each. The drugs were administered daily for 42 days at therapeutic doses (NVP 200 mg/kg, PAR 500 mg/kg, and INH 20 mg/kg) to the respective groups by oral gavage and five rats per group were sacrificed weekly. All the three drugs induced a subclinical liver injury in the first 2-3 weeks followed by healing, indicating adaption. The liver injury was pathologically similar and was associated with immune stimulation and increased cytochrome P450 activity. NVP- and PAR-induced liver injury lasted up to 14 days while that for INH lasted for 28 days. NVP-induced liver injury was associated with increased IL-2, CD4 count, and CYP3A2 activity, followed by increased IL-10 during the healing phase. In conclusion, the initial drug-induced subclinical liver injury, its spontaneous healing, and the associated adaptive immune response have been demonstrated.

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Idiosyncratic Drug-Induced Liver Injury: Mechanistic and Clinical Challenges

International Journal of Molecular Sciences ◽

10.3390/ijms22062954 ◽

2021 ◽

Vol 22 (6) ◽

pp. 2954

Author(s):

Alison Jee ◽

Samantha Christine Sernoskie ◽

Jack Uetrecht

Keyword(s):

Immune Response ◽

Immune System ◽

T Cell ◽

Liver Injury ◽

Clinical Manifestations ◽

Adaptive Immune System ◽

Human Leukocyte ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Adaptive Immune

Idiosyncratic drug-induced liver injury (IDILI) remains a significant problem for patients and drug development. The idiosyncratic nature of IDILI makes mechanistic studies difficult, and little is known of its pathogenesis for certain. Circumstantial evidence suggests that most, but not all, IDILI is caused by reactive metabolites of drugs that are bioactivated by cytochromes P450 and other enzymes in the liver. Additionally, there is overwhelming evidence that most IDILI is mediated by the adaptive immune system; one example being the association of IDILI caused by specific drugs with specific human leukocyte antigen (HLA) haplotypes, and this may in part explain the idiosyncratic nature of these reactions. The T cell receptor repertoire likely also contributes to the idiosyncratic nature. Although most of the liver injury is likely mediated by the adaptive immune system, specifically cytotoxic CD8+ T cells, adaptive immune activation first requires an innate immune response to activate antigen presenting cells and produce cytokines required for T cell proliferation. This innate response is likely caused by either a reactive metabolite or some form of cell stress that is clinically silent but not idiosyncratic. If this is true it would make it possible to study the early steps in the immune response that in some patients can lead to IDILI. Other hypotheses have been proposed, such as mitochondrial injury, inhibition of the bile salt export pump, unfolded protein response, and oxidative stress although, in most cases, it is likely that they are also involved in the initiation of an immune response rather than representing a completely separate mechanism. Using the clinical manifestations of liver injury from a number of examples of IDILI-associated drugs, this review aims to summarize and illustrate these mechanistic hypotheses.

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Characterisation of the Immune Response in Patients with Drug Induced Liver Injury

10.26226/morressier.58eb975cd462b80290b4fa62 ◽

2017 ◽

Author(s):

Giacomo Germani

Keyword(s):

Immune Response ◽

Liver Injury ◽

Drug Induced ◽

Drug Induced Liver Injury

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Characterisation of the immune response in patients with drug induced liver injury

Digestive and Liver Disease ◽

10.1016/j.dld.2017.01.032 ◽

2017 ◽

Vol 49 (1) ◽

pp. e15

Author(s):

C. Bergamo ◽

G. Germani ◽

D. Bizzaro ◽

C. Frasson ◽

G. Basso ◽

...

Keyword(s):

Immune Response ◽

Liver Injury ◽

Drug Induced ◽

Drug Induced Liver Injury

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The Immunological Mechanisms and Immune-Based Biomarkers of Drug-Induced Liver Injury

Frontiers in Pharmacology ◽

10.3389/fphar.2021.723940 ◽

2021 ◽

Vol 12 ◽

Author(s):

Wenhui Liu ◽

Xiangchang Zeng ◽

Yating Liu ◽

Jinfeng Liu ◽

Chaopeng Li ◽

...

Keyword(s):

Immune Response ◽

Liver Injury ◽

New Drugs ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Cellular Events ◽

Immunological Mechanisms ◽

Close Relationship ◽

Life Threatening ◽

Underlying Mechanisms

Drug-induced liver injury (DILI) has become one of the major challenges of drug safety all over the word. So far, about 1,100 commonly used drugs including the medications used regularly, herbal and/or dietary supplements, have been reported to induce liver injury. Moreover, DILI is the main cause of the interruption of new drugs development and drugs withdrawn from the pharmaceutical market. Acute DILI may evolve into chronic DILI or even worse, commonly lead to life-threatening acute liver failure in Western countries. It is generally considered to have a close relationship to genetic factors, environmental risk factors, and host immunity, through the drug itself or its metabolites, leading to a series of cellular events, such as haptenization and immune response activation. Despite many researches on DILI, the specific biomarkers about it are not applicable to clinical diagnosis, which still relies on the exclusion of other causes of liver disease in clinical practice as before. Additionally, circumstantial evidence has suggested that DILI is mediated by the immune system. Here, we review the underlying mechanisms of the immune response to DILI and provide guidance for the future development of biomarkers for the early detection, prediction, and diagnosis of DILI.

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Drug Hepatotoxicity

10.2310/gastro.14006 ◽

2018 ◽

Author(s):

Fernando Bessone ◽

Raúl J Andrade

Keyword(s):

Immune System ◽

Liver Injury ◽

Liver Failure ◽

Acute Liver Failure ◽

Causality Assessment ◽

Adaptive Immune System ◽

Genome Wide Association Studies ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Adaptive Immune

Idiosyncratic drug-induced liver injury (DILI) caused by xenobiotics (drugs, herbals, and dietary supplements) is an elusive liver disease presenting with a range of phenotypes and severity, including acute hepatitis that is indistinguishable from viral hepatitis, autoimmune hepatitis, steatosis, fibrosis or rare chronic vascular syndromes, asymptomatic liver test abnormalities,and acute liver failure. Case definition and characterization using liver biochemistry and histology are crucial for appropriate phenotyping. The incidence of DILI is probably higher than expected by the cases that are identified in clinical practice because of misdiagnosis and underreporting.The pathogenesis of DILI is complex, depending on the interaction of a drug’s physicochemical properties and host factors. Genome-wide association studies have identified several alleles from the major histocompatibility complex system, indicating a fundamental role of the adaptive immune system in DILI pathogenesis. As specific biomarkers for hepatotoxicity are still not available, the diagnosis of DILI remains one of exclusion of the alternative causes of liver damage. Structured causality assessment using the Roussel Uclaf Causality Assessment Method (RUCAM) or previously Council for International Organizations of Medical Sciences (CIOMS) instrument adds consistency to the diagnostic process, although there is room for improvement in the scale domains and score weighting. The therapy for idiosyncratic hepatotoxicity is supportive and relies on the prompt withdrawal of the offending agent. Corticosteroid therapy for hypersensitivity reactions or ursodeoxycholicacid for prolonged cholestasis is empirically used, although the degree of evidence is low. Existing databases have enabled a better prediction of immediate and long-term DILI prognosis. Multivariate models have identified clinical and analytical variables as predictive of acute liver failure and mortality as well as of chronic DILI. This review contains 2 figures, 5 tables, and 55 references Key Words: adaptive immune system; causality assessment; drug-induced liver injury; epidemiology; HLA alleles; pharmacogenetics; registries; risk factors

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Role of the Adaptive Immune System in Idiosyncratic Drug-Induced Liver Injury

Drug-Induced Liver Disease ◽

10.1016/b978-0-12-387817-5.00011-x ◽

2013 ◽

pp. 175-193 ◽

Cited By ~ 4

Author(s):

Jack Uetrecht

Keyword(s):

Immune System ◽

Liver Injury ◽

Adaptive Immune System ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Adaptive Immune

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Hepatocyte-Derived Exosomes Promote Liver Immune Tolerance: Possible Implications for Idiosyncratic Drug-Induced Liver Injury

Toxicological Sciences ◽

10.1093/toxsci/kfz112 ◽

2019 ◽

Vol 170 (2) ◽

pp. 499-508 ◽

Cited By ~ 14

Author(s):

Natalie S Holman ◽

Rachel J Church ◽

Manisha Nautiyal ◽

Kelly A Rose ◽

Sarah E Thacker ◽

...

Keyword(s):

Liver Injury ◽

Immune Tolerance ◽

Target Genes ◽

Normal Liver ◽

T Cell Response ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Adaptive Immune ◽

Immune Attack ◽

Mock Control

Abstract Most idiosyncratic drug-induced liver injury appears to result from an adaptive immune attack on the liver. Recent evidence suggests that the T-cell response may be facilitated by the loss of immune tolerance. In this study, we explored the hypothesis that constitutively released hepatocyte-derived exosomes (HDE) are important for maintaining normal liver immune tolerance. Exosomes were isolated from the conditioned medium of primary human hepatocytes via polymer precipitation. Mock controls were prepared by processing fresh medium that was not hepatocyte exposed with precipitation reagent. THP-1 monocytes were then treated with HDE or an equivalent volume of mock control for 24 h, followed by a 6-h stimulation with LPS. HDE exposure resulted in a significant decrease in the LPS-induced media levels of interleukin-1β and interleukin-8. Gene expression profiling performed in THP-1 cells just prior to LPS-induced stimulation identified a significant decrease among genes associated with innate immune response. MicroRNA (miRNA) profiling was performed on the HDE to identify exosome contents that may drive immune suppression. Many of the predicted mRNA target genes for the most abundant microRNAs in HDE were among the differentially expressed genes in THP-1 cells. Taken together, our data suggest that HDE play a role in maintaining normal liver immune tolerance. Future experiments will explore the possibility that drugs causing idiosyncratic liver injury promote the loss of homeostatic HDE signaling.

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