Immune-mediated Liver Injury Research Articles

Immune-Mediated Hepatitis During Immune Checkpoint Inhibitor cancer Immunotherapy: Lessons From Autoimmune Hepatitis and Liver Immunology.

Immune checkpoint inhibitors (ICI) are being increasingly used to successfully treat several types of cancer. However, due to their mode of action, these treatments are associated with several immune-related adverse events (irAEs), including immune-mediated autoimmune-like hepatitis in 5 to 10% of cases. The specific immune mechanism responsible for the development of immune-mediated liver injury caused by immune checkpoint inhibitors (ILICI) is currently unknown. This review summarizes the current knowledge on hepatic irAEs during cancer immunotherapy. It also addresses the clinical management of ILICI and how it is becoming an increasingly important clinical issue. Clinical, histological, and laboratory features of autoimmune hepatitis (AIH) and ILICI are compared, and their shared and distinctive traits are discussed in an effort to better understand the development of hepatic irAEs. Finally, based on the current knowledge of liver immunology and AIH pathogenesis, we propose a series of events that could trigger the observed liver injury in ICI-treated patients. This model could be useful in the design of future studies aiming to identify the specific immune mechanism(s) at play in ILICI and improve immune checkpoint inhibitor cancer immunotherapy.

Epigenetic Aspects and Prospects in Autoimmune Hepatitis.

The observed risk of autoimmune hepatitis exceeds its genetic risk, and epigenetic factors that alter gene expression without changing nucleotide sequence may help explain the disparity. Key objectives of this review are to describe the epigenetic modifications that affect gene expression, discuss how they can affect autoimmune hepatitis, and indicate prospects for improved management. Multiple hypo-methylated genes have been described in the CD4+ and CD19+ T lymphocytes of patients with autoimmune hepatitis, and the circulating micro-ribonucleic acids, miR-21 and miR-122, have correlated with laboratory and histological features of liver inflammation. Both epigenetic agents have also correlated inversely with the stage of liver fibrosis. The reduced hepatic concentration of miR-122 in cirrhosis suggests that its deficiency may de-repress the pro-fibrotic prolyl-4-hydroxylase subunit alpha-1 gene. Conversely, miR-155 is over-expressed in the liver tissue of patients with autoimmune hepatitis, and it may signify active immune-mediated liver injury. Different epigenetic findings have been described in diverse autoimmune and non-autoimmune liver diseases, and these changes may have disease-specificity. They may also be responses to environmental cues or heritable adaptations that distinguish the diseases. Advances in epigenetic editing and methods for blocking micro-ribonucleic acids have improved opportunities to prove causality and develop site-specific, therapeutic interventions. In conclusion, the role of epigenetics in affecting the risk, clinical phenotype, and outcome of autoimmune hepatitis is under-evaluated. Full definition of the epigenome of autoimmune hepatitis promises to enhance understanding of pathogenic mechanisms and satisfy the unmet clinical need to improve therapy for refractory disease.

Th17/Treg imbalance mediates hepatic intolerance to exogenous lipopolysaccharide and exacerbates liver injury in triptolide induced excessive immune response

Ethnopharmacological relevanceTriptolide (TP) is a major active ingredient and toxic component of Tripterygium wilfordii Hook F (TWHF), which exhibits multiple activities and remarkable hepatotoxicity, the latter of which limits its clinical application due to the risk of liver injury. Previous research has revealed the hepatotoxicity of TP resulting in liver hypersensitivity upon lipopolysaccharide (LPS) stimulation. However, existing research has not elucidated the potential immune mechanism such as Th17/Treg imbalance in TP-induced hepatic excessive immune response to exogenous LPS. Aim of the studyTo investigate the role of Th17/Treg imbalance in TP-induced hepatic excessive immune response to exogenous LPS. Materials and methodsMice were administered with TP, LPS, neutralization antibody and small molecule inhibitor respectively. Serum transaminase level was measured to determine the severity of liver injury. Frequencies of liver Th17 and Treg cells were analyzed by flow cytometry. Serum cytokine levels were performed by ELSIA, and mRNA levels of liver cytokine were performed by qPCR. The status of neutrophil infiltration was performed by myeloperoxidase (MPO) IHC measurement. Morphological observation of liver was performed by hematoxylin and eosin (H&E) staining. ResultsMice given a single intragastric dose of TP (500 μg/kg) developed lethal fulminant hepatitis following intraperitoneal injection of LPS (0.1 mg/kg), characterized by low survival rate, severe liver injury, high levels of inflammation and neutrophil infiltration. Hepatic Th17/Treg imbalance emerged together with liver injury in these mice. Neutralization of IL-17A attenuated the liver injury and ameliorated the neutrophil infiltration. The TP-induced alteration of hepatic Th17/Treg balance was closely related to the outcome of immune-mediated acute liver injury triggered by LPS. Pretreatment with the STAT3 inhibitor AG490 effectively restored Th17/Treg balance, significantly reducing the production of IL-17A and finally attenuating the degree of liver injury. ConclusionHepatic Th17/Treg imbalance not only exacerbates TP- and LPS-induced liver injury, but also serves as an indispensable part in the mechanisms of TP-induced hepatic intolerance to exogenous endotoxin.

Human liver stem cells alleviate Con-A induced liver injury by regulating the balance of Treg/Th17 cells

BackgroundLiver injury is a serious threat to human health that has become a worldwide problem. To date, there is still no effective treatment strategy. In the present study, we examined the protective effects of Human liver stem cells (HLSCs) against concanavalin A (Con A)-induced acute liver injury. MethodsIsolated HLSCs were characterized by microscopy, functional assays, and gene expression. HLSCs or HLSCs culture medium were transplanted in mice for 12 h and subsequently challenged with Con A via tail-vein injection. The effects were evaluated through survival rate, histology, blood tests, TUNEL assay, quantitative RT-PCR and flow cytometry. CellTracker™ CM-Dil labled HLSCs were tracked by fluorescence microscope. ResultsTransplantation of HLSCs reduced the mortality rate, reduced the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL), narrowed the area of liver necrosis, and inhibited hepatocyte apoptosis induced by Con A. Injection of HLSCs culture medium could also alleviate Con A-induced liver injury. Of note, HLSCs-transplanted mice exhibited lower frequencies of Th17 cells and higher frequencies of Tregs in their liver and spleen following Con A injection. Moreover, transplantation of HLSCs significantly reduced the expression of IL-17A, IL-17F and ROR-γt induced by Con A, while reversed Con A-induced downregulation of Foxp3 expression and IL-10. ConclusionsHLSCs protect mice from immune-mediated liver injury by regulating the balance of Treg/Th17 cells, suggesting that transplantation of HLSCs is a potential and effective therapeutic method for amelioration of liver injury.

Immune-mediated liver injury following COVID-19 vaccination: A systematic review.

Immune‐mediated liver injury (ILI) following coronavirus disease 2019 (COVID‐19) vaccination is not well‐characterized. Therefore, we systematically reviewed the literature on ILI after COVID‐19 vaccination. We searched PubMed, Cochrane, Ovid, Embase, and gray literature to include articles describing ILI following COVID‐19 vaccination. Reports without confirmatory evidence from liver biopsy were excluded. Descriptive analysis, and study quality were reported as appropriate. Of the 1,048 articles found, 13 (good/fair quality; 23 patients) were included. Studies were primarily from Europe (n = 8), America (n = 2), Asia (n = 2), or Australia (n = 1). Patients were predominantly females (62.5%) of age 55.3 years (49.1–61.4), with an antecedent exposure to Moderna messenger RNA (mRNA)–1273 (47.8%), Pfizer‐BioNTech BNT162b2 mRNA (39.2%), or ChAdOx1 nCoV‐19 vaccine (13%). Pre‐existing comorbidities (69.6%) were common, including liver disease in 26.1% and thyroid disorders in 13% of patients. About two‐thirds of the patients were on concurrent medications (paracetamol, levothyroxine, statins, and non‐steroidal anti‐inflammatory drugs). Jaundice was the most common symptom (78.3%). Peak bilirubin, alanine aminotransferase, and alkaline phosphatase levels were 10.8 (6.8–14.8) mg/dl, 1,106.5 (757.0–1,702.5) U/L, and 229 (174.6–259.6) U/L, respectively. Histological findings were intense portal lymphoplasmacytic infiltrate with interface hepatitis. Steroids were used in 86.9% of patients, and complete response, recovering course, and death were reported in 56.5%, 39.1%, and 4.3% of patients, respectively. ILI following COVID‐19 vaccination is rare. The diagnosis is established on temporal correlation, biochemical findings, and histopathology. Prognosis is excellent with corticosteroids. Causality establishment remains a challenge.

The use of transient elastography in identifying sub-clinical chronic ductopenic rejection in adult liver transplant recipients: A case series

BackgroundTransient elastography has become a standard tool for the accurate non-invasive assessment of liver stiffness and fat content. Liver transplant recipients can develop allograft fibrosis during long-term follow-up despite normal or mildly abnormal liver chemistries. Tapering of immunosuppression in long-term liver transplant survivors is performed relying solely on liver chemistries. It is important to know if underlying liver histology would be abnormal or if rejection was present as this would alter the desire to decrease stable maintenance doses of immunosuppression. MethodsWe present our experience of five liver transplant recipients who had transient elastography performed prior to consideration of weaning of their immunosuppression. ResultsAll five patients showed signs of elevated liver stiffness on transient elastography in the setting of normal to slightly abnormal liver tests with very stable immunosuppressant doses. This prompted the performance of liver biopsies which demonstrated immune-mediated liver injury and thus negated the immunosuppression withdrawal. ConclusionTransient elastography has utility as a non-invasive method to evaluate allograft health in long-term liver transplant survivors and can be useful in the decision-making process for immunosuppression weaning.

Continuous Activation of Dopamine Receptors Alleviates LPS-Induced Liver Injury in Mice via β-arrestin2 Dependent Akt/NF-κB Pathway.

Many studies showed that dopamine receptors (DRs) agonists have anti-inflammatory effects. Rotigotine, a non-ergot dopamine receptor agonist, mainly actives DRD2/DRD3/DRD1. Rotigotine extended-release microspheres (RoMS) are a sustained-release formulation that can release sustainably rotigotine for more than 7 days after a single dose of RoMS. This study aimed to investigate whether RoMS can attenuate the lipopolysaccharide (LPS)-induced liver injury of mice. The liver injury was evaluated by assaying serum transaminase and observing histopathological changes. The levels of pro-inflammatory cytokines in serum were also detected. Western blot was employed to assay the expression of proteins in the Akt/NF-κB pathway. The results showed that pre-administration with a single dose of RoMS could inhibit the increase of serum transaminase induced by LPS, alleviate the pathological damage of liver tissue, and decrease the levels of tumor necrosis factor-α and interleukin-6. In addition, RoMS decreased Toll-like receptor 4 protein expression in liver tissue. RoMS mitigated liver injury by activating DRs and negatively regulating the β-arrestin2-dependent Akt/NF-κB signaling pathway. The effects of RoMS could be weakened or abolished by the specific DRD2 antagonist, R121. In conclusion, activation of DRs inhibited the releases of pro-inflammatory cytokines and alleviated the immune-mediated liver injury induced by LPS in mice. The anti-inflammatory mechanism of RoMS may be related to the regulation of the β-arrestin2-dependent Akt/NF-κB signaling pathway.

Infrequent liver injury from cemiplimab in patients with advanced cutaneous squamous cell carcinoma.

Aim: To describe the incidence and outcomes of liver injury in patients with advanced cutaneous squamous cell carcinoma (cSCC) receiving cemiplimab. Methods: Charts of cSCC patients receiving cemiplimab between 28 September2018and 14 July2020 were reviewed. Liver injury was determined using laboratory criteria, and causality assessment was completed. Results: Of 39 cemiplimab-treated patients, four(10.3%) developed liver injury. Two cases of hepatotoxicitywere attributed to immune-mediated liver injury caused by cemiplimab and the twoother caseswere attributed to other causes. The fourpatients with liver injury had tumor responses and survival similar to those of the patients without liver injury. Conclusion: Liver injury arising during cemiplimab therapy is mild and infrequent in cSCC patients. Due to its favorable safety profile, cemiplimab should be considered in patients with cSCC and pre-existing liver disease.

Letter to the editor: Liver transplantation following severe acute respiratory syndrome‐coronavirus‐2 vaccination–induced liver failure

Several case reports have described development of liver injury following severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccination in Hepatology.[1, 2] These cases showed autoimmune hepatitis (AIH) features, and all cases responded well to corticosteroid therapy. Herein, we present a patient who underwent liver transplantation due to fulminant liver failure following vaccination with the BioNTech vaccine. A 53-year-old previously healthy man received a first dose of BioNTech vaccine on the June 5, 2021. Ten days after vaccination, he developed mild abdominal pain, erythematous skin eruption, and pruritus. Initial laboratory findings were alanine aminotransferase (ALT) 333 (upper limit of normal [ULN] 55 U/L), aspartate aminotransferase (AST) 168 (ULN 34 U/L), alkaline phosphatase 102 (ULN 150 U/L), and total bilirubin 0.8 (ULN 1.2 mg/dl). The patient’s symptoms were considered to be a hypersensitivity reaction. Oral antihistaminic therapy and topical steroids did not lead to clinical improvement. On day 18 after vaccination, prednisolone 32 mg/day for 10 days followed by 16 mg/day for 20 days was commenced. One week into the steroid course, symptoms significantly improved, and aminotransferases decreased (Figure 1). The patient was reluctant to receive a second vaccine dose for fear of additional side effects but had travel plans and needed a full vaccination chart. He, therefore, scheduled a second Pfizer-BioNTech vaccine dose 6 weeks after the first dose. Following the second vaccination, similar symptoms reoccurred after a few days. The dose of prednisolone was increased to 32 mg/day, gradually tapered, and discontinued in mid-August 2021. One month after, he developed abdominal pain, myalgia, fatigue, and jaundice. The symptoms and laboratory findings did not improve over 10 days, and he was referred to a tertiary liver transplant center. At admission, ALT was 485, AST was 629, total bilirubin was 6.6 mg/dl, and the international normalized ratio was 1.36. Serum IgG levels were 28.3 (7.0–16.4 g/L). Viral serology was negative for hepatitis A–E, Epstein-Barr virus, cytomegalovirus, and herpes simplex virus. Antinuclear antibodies, smooth muscle actin, antimitochondrial antibodies, anti–liver–kidney microsome 1, liver cytosolic antigen 1, and anti–soluble liver antigen were all negative; and ceruloplasmin was normal. The liver biopsy showed portal inflammation with interface activity and significant lobular necroinflammatory activity, hepatocellular rosette formation and emperipolesis that are typical components of AIH. Treatment with prednisolone (40 mg/day, i.v.) and plasma exchange did not improve the liver function. The patient developed HE and underwent living donor liver transplantation. One month after liver transplantation, he was alive with significantly improved laboratory findings. We presented a report of severe outcome of liver injury that developed after SARS-CoV-2 vaccination. We are aware that it is difficult to establish a definitive causality between SARS-CoV-2 vaccine and hepatitis. However, our case demonstrates strong evidence of vaccine-induced immune-mediated liver injury. The patient developed liver injury after a first dose of Pfizer-BioNTech vaccine which on reexposure led to severe liver injury. Our case, along with other reports, suggests that AIH-like hepatitis may develop after SARS-CoV-2 vaccination. Early diagnosis and effective management seem to be very important in this emerging condition. Nothing to report. Cumali Efe, Murat Harputluoğlu, and Sezai Yilmaz conceptualized the study. Cumali Efe, Murat Harputluoğlu, and Neşe Karadağ Soylu collected and analyzed data. All authors approved the final version of the manuscript. All data that support the findings of this study are presented in the text.

E2f2 Attenuates Apoptosis of Activated T Lymphocytes and Protects from Immune-Mediated Injury through Repression of Fas and FasL.

Targeted disruption of E2f2 in mice causes T-cell hyperactivation and a disproportionate cell cycle entry upon stimulation. However, E2f2−/− mice do not develop a lymphoproliferative condition. We report that E2f2 plays a Fas-dependent anti-apoptotic function in vitro and in vivo. TCR-stimulated murine E2f2−/− T cells overexpress the proapoptotic genes Fas and FasL and exhibit enhanced apoptosis, which is prevented by treatment with neutralizing anti-FasL antibodies. p53 pathway is activated in TCR-stimulated E2f2−/− lymphocytes, but targeted disruption of p53 in E2f2−/− mice does not abrogate Fas/FasL expression or apoptosis, implying a p53-independent apoptotic mechanism. We show that E2f2 is recruited to Fas and FasL gene promoters to repress their expression. in vivo, E2f2−/− mice are prone to develop immune-mediated liver injury owing to an aberrant lymphoid Fas/FasL activation. Taken together, our results suggest that E2f2-dependent inhibition of Fas/FasL pathway may play a direct role in limiting the development of immune-mediated pathologies.

Thymoquinone Attenuates Immune Mediated Liver Injury Induced by Concanavalin A in Mice

Autoimmune hepatitis is an inflammatory disease and its incidence has been increasing. The features of hepatitis are the release of inflammatory cytokines, the elevation of AST and ALT, and hepatocyte apoptosis and necrosis. Concanavalin A considered as essential model represents the acute immune-mediated liver damage in rodents. Thymoquinone is well known herbal compound that exert hepatoprotective, anti-inflammatory, and antioxidant activity. In this study, we focus on the immunoregulatory and liver protective effect of thymoquinone in a mouse model of concanavalin A-induced liver injury.
 Twenty-four male mice were randomly divided into four groups each containing six animals: Negative control group, concanavalin A model group, thymoquinone 15mg/kg group, and thymoquinone 30mg/kg group. Blood was collected to detect the activities of alanine transaminase (ALT) and aspartate transaminase (AST) as well as liver tissue for the detection of tumor necrosis factor 
 levels, after 8 hours of concanavalin A injection.
 Injecting mice with concanavalin resulted in a dramatic increase in serum level of both ALT and AST which indicate severe liver tissue damage with a significant increase in inflammatory cytokines TNF alpha -
 and INF levels, with a notable increase in NF-kB gene expression in mice liver tissue homogenate. Thymoquinone pretreatment revealed a dose-dependent increase in liver tissue protection.
 Conclusion: Thymoquinone has hepatoprotective and immune modulatory effects in concanavalin A induced immune mediated liver damage. Thymoquinone exerted its effect through attenuating NF and its downstream effectors TNF and INF in a dose dependent manner.

Activation of AMPKα1 is essential for regulatory T cell function and autoimmune liver disease prevention.

Regulatory T cells (Treg cells) are crucial for maintaining immune tolerance. Compromising the regulatory function of Treg cells can lead to autoimmune liver disease. However, how Treg cell function is regulated has not been fully clarified. Here, we report that mice with AMP-activated protein kinase alpha 1 (AMPKα1) globally knocked out spontaneously develop immune-mediated liver injury, with massive lymphocyte infiltration in the liver, elevated serum alanine aminotransferase levels, and greater production of autoantibodies. Both transplantation of wild-type bone marrow and adoptive transfer of wild-type Treg cells can prevent liver injury in AMPKα1-KO mice. In addition, Treg cell-specific AMPKα1-KO mice display histological features similar to those associated with autoimmune liver disease, greater production of autoantibodies, and hyperactivation of CD4+ T cells. AMPKα1 deficiency significantly impairs Treg cell suppressive function but does not affect Treg cell differentiation or proliferation. Furthermore, AMPK is activated upon T cell receptor (TCR) stimulation, which triggers Foxp3 phosphorylation, suppressing Foxp3 ubiquitination and proteasomal degradation. Importantly, the frequency of Treg cells and the phosphorylation levels of AMPK at T172 in circulating blood are significantly lower in patients with autoimmune liver diseases. Conclusion: Our data suggest that AMPK maintains the immunosuppressive function of Treg cells and confers protection against autoimmune liver disease.

Hepatic immune-mediatedadverseeffects of immune checkpoint inhibitors: analysis of real-life experience

Introduction and objectivesImmune Checkpoint Inhibitors (ICI) have shifted the paradigm of cancer therapy treatment. Despite their efficacy, ICIs may induce immune-related adverse events (irAE), which can affect various organs, namely the liver. This study intends to perform a comprehensive clinical description of the hepatic irAEs associated with ICI in a Portuguese population of a tertiary hospital centre. Materials and methodsA retrospective analysis of patients who developed immune-mediated liver injury (IMLI), among a cohort of patients treated with ICIs between March 15th of 2015 and December 15th of 2019 in a tertiary hospital. We used both Common Terminology Criteria for Adverse Events (CTCAE) and Drug‐Induced Liver Injury Network (DILIN) criteria to define liver injury. ResultsAmong 151 patients, eight (5.3%) patients developed liver injury grade ≥3, of which five had hepatic metastasis. As such, only 3 cases were classified as IMLI. All IMLI presented with cholestasis pattern; the median duration from ICI initiation to IMLI was 84 days and/or 4 ICI cycles; one patient registered IMLI one month after nivolumab suspension; all were treated with steroids and one was successfully submitted to ICI re-challenge; a favourable outcome was seen in all patients; the median time to hepatic biochemistries normalization was 150 days. Among 10 patients with previous hepatic conditions, only one developed liver injury grade 2. ConclusionsClinically significant ICI-related hepatotoxicity was uncommon; Immune-mediated liver injury may present a cholestatic pattern predominance. There was a low rate of liver injury of any kind in patients with previous hepatic disease while on ICI.

Glucosylceramide synthase regulates hepatocyte repair after concanavalin A-induced immune-mediated liver injury.

BackgroundSphingolipids produce pleiotropic signaling pathways, and participate in the pathological mechanism of hepatocyte apoptosis and necrosis during liver injury. However, the role of glucosylceramide synthase (GCS)–key enzyme that catalyzes the first glycosylation step, in liver injury is still vague.MethodsAll experiments were conducted using 7–9-week-old pathogen-free male C57BL/6 mice. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were detected in murine models of liver disease, in addition to histological characterization of liver injuries. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the relative expression of the GCS, matrix metallopeptidase-1 (MMP-1), and tissue inhibitor of metalloproteinase-1 (TIMP-1) genes. The GCS was observed through a fluorescence microscope, and the flow cytometry was used to detect hepatocyte apoptosis. The concentrations of serum IL-4, IL-6, and IL-10 were measured using enzyme-linked immune-sorbent assay (ELISA) kit. MMP-1 and TIMP-1 protein expression was measured via western blot (WB) analysis.ResultsCon A is often used as a mitogen to activate T lymphocytes and promote mitosis. A single dose of Con A injected intravenously will cause a rapid increase of ALT and AST, which is accompanied by the release of cytokines that cause injury and necrosis of hepatocytes. In this study, we successfully induced acute immune hepatitis in mice by Con A. Con A administration resulted in GCS upregulation in liver tissues. Moreover, the mice in the Con A group had significantly higher levels of ALT, AST, IL-4, IL-6, IL-10 and increased hepatocyte apoptosis than the control group. In contrast, all of the aforementioned genes were significantly downregulated after the administration of a GCS siRNA or Genz-123346 (i.e., a glucosylceramide synthase inhibitor) to inhibit the GCS gene. Additionally, the histopathological changes observed herein were consistent with our ALT, AST, IL-4, IL-6, and IL-10 expression results. However, unlike this, hepatocyte apoptosis has been further increased on the basis of the Con A group. Moreover, our qRT-PCR and WB results indicated that the expression of MMP-1 in the Con A group was significantly lower than that in the control group, whereas TIMP-1 exhibited the opposite trend. Conversely, MMP-1 expression in the GCS siRNA and Genz-123346 groups was higher than that in the Con A group, whereas TIMP-1 expression was lower.ConclusionsGCS inhibition reduces Con A-induced immune-mediated liver injury in mice, which may be due to the involvement of GCS in the hepatocyte repair process after injury.

Deciphering the Dynamic Complexities of the Liver Microenvironment - Toward a Better Understanding of Immune-Mediated liver Injury Caused by Immune Checkpoint Inhibitors (ILICI).

Immune checkpoint inhibitors (ICIs) represent a promising therapy for many types of cancer. However, only a portion of patients respond to this therapy and some patients develop clinically significant immune-mediated liver injury caused by immune checkpoint inhibitors (ILICI), an immune-related adverse event (irAE) that may require the interruption or termination of treatment and administration of systemic corticosteroids or other immunosuppressive agents. Although the incidence of ILICI is lower with monotherapy, the surge in combining ICIs with chemotherapy, targeted therapy, and combination of different ICIs has led to an increase in the incidence and severity of ILICI - a major challenge for development of effective and safe ICI therapy. In this review, we highlight the importance and contribution of the liver microenvironment to ILICI by focusing on the emerging roles of resident liver cells in modulating immune homeostasis and hepatocyte regeneration, two important decisive factors that dictate the initiation, progression, and recovery from ILICI. Based on the proposed contribution of the liver microenvironment on ICILI, we discuss the clinical characteristics of ILICI in patients with preexisting liver diseases, as well as the challenges of identifying prognostic biomarkers to guide the clinical management of severe ILICI. A better understanding of the liver microenvironment may lead to novel strategies and identification of novel biomarkers for effective management of ILICI.

Alteration of Gut Microbiota and Its Impact on Immune Response in Patients with Chronic HBV Infection: A Review.

Chronic hepatitis B virus infection is a source of substantial global health problems, particularly in economically underdeveloped and/or developing countries. It is the primary cause of severe liver disorders such as liver fibrosis, cirrhosis, and hepatocellular carcinoma. The liver is connected by the bile duct to the small intestine that carries bile produced in the liver to the intestine. The liver is the initial organ exposed to materials originating from the gut including dietary compounds, bacteria, and their products. Human intestines harbor a wide diversity of the community of microbes which are collectively termed as gut microbiota. In chronic infection with the hepatitis B virus, microbial alteration of the gut is a source of systemic immune activation. Besides, gut permeability is altered in hepatitis B virus-infected patients with an increased bacterial translocation and endotoxin load in the portal vein that caused toll-like receptor activation in the liver, which facilitates immune-mediated liver injury. Toll-like receptors further triggered the host-wide inflammatory response by inducing signaling cascades such as nuclear factor-kappa B-linked pathways and by accelerating cytokine secretion like tumor necrosis factor-alpha, which evokes chronic inflammation and leads to liver lesion formation, fibrosis progression, and cirrhosis and hepatocellular carcinoma development. In conclusion, changes in intestinal flora play an important role in encouraging the production of chronic infection with the hepatitis B virus. Therefore, careful attention should be given to the maintenance of intestinal microecology of patients which can provide a sound foundation for the treatment of chronic infection with the hepatitis B virus.

Immune-Mediated Drug-Induced Liver Injury: Immunogenetics and Experimental Models.

Drug-induced liver injury (DILI) is a challenging clinical event in medicine, particularly because of its ability to present with a variety of phenotypes including that of autoimmune hepatitis or other immune mediated liver injuries. Limited diagnostic and therapeutic tools are available, mostly because its pathogenesis has remained poorly understood for decades. The recent scientific and technological advancements in genomics and immunology are paving the way for a better understanding of the molecular aspects of DILI. This review provides an updated overview of the genetic predisposition and immunological mechanisms behind the pathogenesis of DILI and presents the state-of-the-art experimental models to study DILI at the pre-clinical level.

Recent Advances in Models of Immune-Mediated Drug-Induced Liver Injury

Hepatic inflammation is a key feature of a variety of liver diseases including drug-induced liver injury (DILI), orchestrated by the innate immune response (Kupffer cells, monocytes, neutrophils, dendritic cells) and the adaptive immune system (T cells and natural killer T cells). In contrast to acute DILI, prediction of immune-mediated DILI (im-DILI) has been more challenging due to complex disease pathogenesis, lack of reliable models and limited knowledge of underlying mechanisms. This review summarizes in vivo and in vitro systems that have been used to model im-DILI. In particular, the review focuses on state-of-the-art in vitro human-based multicellular models which have been developed to supplement the use of in vivo models due to interspecies variation and increasing ethical concerns regarding animal use. Advantages of the co-cultures in maintaining hepatocyte functions and importantly, introducing heterotypic cell-cell interactions to mimic inflammatory hepatic microenvironment are discussed. Challenges regarding cell source and incorporation of different cells with physical cell-cell contact are outlined and potential solutions are proposed. It is likely that better understanding of the interplay of immune cells in liver models will allow for the development of more accurate systems to better predict hepatotoxicity and stratification of drugs that can cause immune-mediated effects.

The Role of Hypoxia-Induced Mitogenic Factor in Organ-Specific Inflammation in the Lung and Liver: Key Concepts and Gaps in Knowledge Regarding Molecular Mechanisms of Acute or Immune-Mediated Liver Injury

Hypoxia-induced mitogenic factor (HIMF), which is also known as resistin-like molecule α (RELM-α), found in inflammatory zone 1 (FIZZ1), or resistin-like alpha (retlna), is a cysteine-rich secretory protein and cytokine. HIMF has been investigated in the lung as a mediator of pulmonary fibrosis, inflammation and as a marker for alternatively activated macrophages. Although these macrophages have been found to have a role in acute liver injury and acetaminophen toxicity, few studies have investigated the role of HIMF in acute or immune-mediated liver injury. The aim of this focused review is to analyze the literature and examine the effects of HIMF and its human homolog in organ-specific inflammation in the lung and liver. We followed the guidelines set by PRISMA in constructing this review. The relevant checklist items from PRISMA were included. Items related to meta-analysis were excluded because there were no randomized controlled clinical trials. We found that HIMF was increased in most models of acute liver injury and reduced damage from acetaminophen-induced liver injury. We also found strong evidence for HIMF as a marker for alternatively activated macrophages. Our overall risk of bias assessment of all studies included revealed that 80% of manuscripts demonstrated some concerns in the randomization process. We also demonstrated some concerns (54.1%) and high risk (45.9%) of bias in the selection of the reported results. The need for randomization and reduction of bias in the reported results was similarly detected in the studies that focused on HIMF and the liver. In conclusion, we propose that HIMF could be utilized as a marker for M2 macrophages in immune-mediated liver injury. However, we also detected the need for randomized clinical trials and additional experimental and human prospective studies in order to fully comprehend the role of HIMF in acute or immune-mediated liver injury.

Mesenchymal stem cells alleviate experimental immune-mediated liver injury via chitinase 3-like protein 1-mediated T cell suppression

Liver diseases with different pathogenesis share common pathways of immune-mediated injury. Chitinase-3-like protein 1 (CHI3L1) was induced in both acute and chronic liver injuries, and recent studies reported that it possesses an immunosuppressive ability. CHI3L1 was also expressed in mesenchymal stem cells (MSCs), thus we investigates the role of CHI3L1 in MSC-based therapy for immune-mediated liver injury here. We found that CHI3L1 was highly expressed in human umbilical cord MSCs (hUC-MSCs). Downregulating CHI3L1 mitigated the ability of hUC-MSCs to inhibit T cell activation, proliferation and inflammatory cytokine secretion in vitro. Using Concanavalin A (Con A)-induced liver injury mouse model, we found that silencing CHI3L1 significantly abrogated the hUC-MSCs-mediated alleviation of liver injury, accompanying by weakened suppressive effects on infiltration and activation of hepatic T cells, and secretion of pro-inflammatory cytokines. In addition, recombinant CHI3L1 (rCHI3L1) administration inhibited the proliferation and function of activated T cells, and alleviated the Con A-induced liver injury in mice. Mechanistically, gene set enrichment analysis showed that JAK/STAT signalling pathway was one of the most significantly enriched gene pathways in T cells co-cultured with hUC-MSCs with CHI3L1 knockdown, and further study revealed that CHI3L1 secreted by hUC-MSCs inhibited the STAT1/3 signalling in T cells by upregulating peroxisome proliferator-activated receptor δ (PPARδ). Collectively, our data showed that CHI3L1 was a novel MSC-secreted immunosuppressive factor and provided new insights into therapeutic treatment of immune-mediated liver injury.