Lamina propria interleukin 17 A aggravates natural killer T-cell activation in autoimmune hepatitis.

Autoimmune hepatitis is an interface hepatitis characterized by the progressive destruction of the liver parenchyma, the cause of which is still obscure. Interleukin (IL)-17A is a major driver of autoimmunity, which can be produced by innate immune cells against several intracellular pathogens. Here, we investigated the involvement of IL-17A in a mice model of immune-mediated hepatitis with the intestine exposed to Salmonella typhimurium. Our results showed more severe Concanavalin (Con) A-induced liver injury and gut microbiome dysbiosis when the mice were treated with a gavage of S. typhimurium. Then, the natural killer (NK) T cells were overactivated by the accumulated IL-17A in the liver in the Con A and S. typhimurium administration group. IL-17A could activate NKT cells by inducing CD178 expression via IL-4/STAT6 signaling. Furthermore, via the portal tract, the laminae propria mucosal-associated invariant T (MAIT)-cell-derived IL-17A could be the original driver of NKT cell overactivation in intragastric administration of S. typhimurium and Con A injection. In IL-17A-deficient mice, Con A-induced liver injury and NKT cell activation were alleviated. However, when AAV-sh-mIL-17a was used to specifically knock down IL-17A in liver, it seemed that hepatic IL-17a knock down did not significantly influence the liver injury. Our results suggested that, under Con A-induction, laminae propria MAIT-derived IL-17A activated hepatic NKT, and this axis could be a therapeutic target in autoimmune liver disease.

The HVEM-BTLA Immune Checkpoint Restrains Murine Chronic Cholestatic Liver Injury by Regulating the Gut Microbiota.

The herpes virus entry mediator (HVEM) is an immune checkpoint molecule regulating immune response, but its role in tissue repair remains unclear. Here, we reported that HVEM deficiency aggravated hepatobiliary damage and compromised liver repair after 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced injury. A similar phenotype was observed in B and T lymphocyte attenuator (BTLA)-deficient mice. These were correlated with impairment of neutrophil accumulation in the liver after injury. The hepatic neutrophil accumulation was regulated by microbial-derived secondary bile acids. HVEM-deficient mice had reduced ability to deconjugate bile acids during DDC-feeding, suggesting a gut microbiota defect. Consistently, both HVEM and BTLA deficiency had dysregulated intestinal IgA responses targeting the gut microbes. These results suggest that the HVEM-BTLA signaling may restrain liver injury by regulating the gut microbiota.

FOXO4 ameliorates alcohol-induced chronic liver injury via inhibiting NF-κB and modulating gut microbiota in C57BL/6J mice.

BACKGROUND: Intestinal mucosa barrier function and gut-liver axis are impaired by ethanol in chronic alcoholic liver disease (ALD). However, the possible mechanism is not clear. This study aimed to investigate the effects of Forkhead Box O4 (FOXO4) on alcohol-induced chronic liver injury and its molecular mechanism(s). METHODS: Male C57BL/6J mice were injected with or without FOXO4-WT, FOXO4-TB or NF-κB vectors, and fed with Lieber-DeCarli liquid diets containing 36% ethanol for eight weeks to induce chronic ALD. Thereafter, blood, liver, colon and fecal samples were collected. Biochemical parameters, endotoxin and inflammatory cytokines in the blood and antioxidant enzymes in the liver were tested by commercial kits. Histopathological changes in the liver were evaluated by HE staining. In addition, the mRNA and protein expression of FOXO4, NF-κB, ZO-1 and Occluding in the colon were measured by quantitative real-time PCR and Western blot, respectively. Furthermore, gut microbiota composition in the fecal samples was investigated with 16S rDNA sequencing. RESULTS: FOXO4 significantly ameliorated liver histopathological damage. Moreover, FOXO4 reduced the serum endotoxin, biochemical parameters (ALT, AST, ALP and TG), antioxidant enzymes (ROS and MDA), inflammatory cytokines (IL-6, IL-1ß, and TNF-α), but restored the levels of GSH, SOD and IL-10. Furthermore, FOXO4 significantly inhibited the expression of NF-κB, p-NF-κB p65, p-IKKα and p-IKKß, and up-regulated the expression of ZO-1 and Occludin. Additionally, FOXO4 modulated the gut microbiota composition and certain bacteria including Odoribacter, Parasutterella and Psychrobacter. CONCLUSION: These findings suggest that FOXO4 protects against alcohol-induced chronic liver injury via inhibiting NF-κB and modulating gut microbiota in C57BL/6J mice.

Apolipoprotein A4 regulates the immune response in carbon tetrachloride-induced chronic liver injury in mice.

This article explores the role of ApoA4 in a CCl4-induced chronic liver injury (CLI) mouse model. C57BL/6J mice (WT) and ApoA4 knock-out (KO) mice were divided into CCl4 CLI (WT-CCl4 and KO-CCl4) and olive oil solvent control groups (WT-Veh and KO-Veh). Some of the KO-CCl4 mice were additionally treated with recombinant mouse ApoA4 and primary mouse T lymphocyte injections. After 6 weeks, histological analyses, biochemical and superoxide dismutase (SOD) and malondialdehyde (MDA) assays, flow cytometry of immune cells and qRT-PCR analyses were performed. KO mice after treatment with CCl4 showed reduced hepatic SOD and enhanced serum MDA activities leading to worsening liver injury and fibrosis compared with WT-CCl4, accompanied by enhanced hepatic alpha smooth muscle actin (α-SMA), tissue inhibitor of metalloproteinases-1 (TIMP-1) and collagen type I alpha 1 chain (COL1A1) transcriptions, elevated macrophage M1 levels, enhanced tumor necrosis factor-alpha (TNF-α), Interleukin 6 (IL-6) and C-C Motif Chemokine Ligand 5 (CCL5), but reduced Interleukin 10 (IL-10), monocyte chemotactic protein 1 (MCP-1), C-C Motif Chemokine Receptor 2 (CCR2), C-X3-C Motif Chemokine Receptor 1 (CX3CR1) and C-X-C Motif Chemokine Ligand 9 (CXCL9) transcription, as well as reduced CD3+, CD4+ and CD8+ T cell percentages in hepatic tissue, blood cells and spleen. In addition, CD11b+CD115+, CD11b+/Ly6Chigh, CD11b+/LyC6- and CD11b+/Ly6Cint cells were enhanced, which partly reversed by ApoA4 protein and T cell injections. In conclusion, we propose that ApoA4 might be involved in liver protection via inhibiting fibrotic mediators and inflammatory cytokines, suppression of pro-inflammatory hepatic M1 cell invasion and regulation of CD8+ T and CD4+ T lymphocytes.

Crocin ameliorates methotrexate-induced liver injury via inhibition of oxidative stress and inflammation in rats.

BACKGROUND: Methotrexate (MTX) is used commonly in the treatment of various cancers and inflammatory diseases; nevertheless, the associated hepatotoxicity has limited its clinical application. Crocin (CRO) is described as a natural carotenoid with analgesic, antioxidant, and antiinflammatory properties. This study aimed to determine the effects of CRO on MTX-induced hepatotoxicity. METHODS: For pretreatment, CRO at doses of 25 and 50 mg/kg (po), as well as 20 mg/kg (ip) of MTX, was injected in rats. RESULTS: MTX led to hepatotoxicity, as confirmed by the significant increase in liver markers, histopathological changes, decreased GSH content, and reduced antioxidant enzyme activity (i.e., CAT, SOD, and GPx). It increased TNF-α, IL-1ß, lipid peroxidation, and nitric oxide levels. Nevertheless, by increasing antioxidant defense in hepatic tissues and reducing oxidative stress and proinflammatory mediators, pretreatment with CRO could alleviate hepatotoxicity. CONCLUSION: CRO can inhibit MTX-induced hepatotoxicity through improving antioxidant defense and reducing oxidative stress and inflammation.

Type 3 cytokines in liver fibrosis and liver cancer.

The type 3 cytokines IL-17 and IL-22 play a crucial, well synchronized physiological role in wound healing and repairing tissue damage due to infections or injury at barrier surfaces. These cytokines act on epithelial cells to induce secretion of early immune mediators, recruitment of inflammatory cells to the site of injury, and to trigger tissue repair mechanisms. However, if the damage persists or if these cytokines are dysregulated, then they contribute to a number of inflammatory pathologies, autoimmune conditions and cancer. The liver is a multifunctional organ that plays an essential role in metabolism, detoxification, and immune surveillance. It is also exposed to a variety of pathogens, toxins and injuries. Over the past decade, IL-17 and IL-22 have been implicated in various aspects of liver inflammation. IL-17 is upregulated in chronic liver injury and associated with liver disease progression. In contrast, IL-22 was shown to be hepatoprotective during acute liver injury but exhibited inflammatory effects in other models. Furthermore, IL-22 and IL-17 are both associated with poor prognosis in liver cancer. Finally, the regulatory mechanisms governing the physiological versus the pathological role of these two cytokines during acute and chronic liver injury remain poorly understood. In this review, we will summarize the current state of knowledge about IL-17 and IL-22 in wound healing during acute and chronic liver injury, their contribution to pathogenesis, their regulation, and their role in the transition from advanced liver disease to liver cancer.

miR-27b-3p, miR-181a-1-3p, and miR-326-5p are involved in the inhibition of macrophage activation in chronic liver injury.

Macrophages are central players in inflammation, which leads to liver injury. It has been reported that continuous macrophage activation initiates this process. Our previous data show that the anti-inflammatory factor, 15-deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2), inhibits bone marrow (BM)-derived macrophage (BMM) migration and inflammatory cytokine production. However, the underlying mechanism of 15d-PGJ2 inhibited BMM activation is still unclear. Here, we evaluate the role of 15d-PGJ2/PPARγ axis in BMM activation. 15d-PGJ2 reduced activated BMM population in injured livers. Inflammatory cytokine expressions (MIP-1ß, TNF-α, NOS2) were depressed by 15d-PGJ2 in macrophages isolated from treated livers. In vitro, 15d-PGJ2 inhibited BMM activation via PPARγ. Moreover, miR-27b-3p, miR-181a-1-3p, and miR-326-5p target MIP-1ß, TNF-α, and NOS2 mRNA, respectively. The miRNA expressions were decreased in damaged livers, macrophages isolated from injured livers, and activated BMMs, which were renewed by 15d-PGJ2/PPARγ axis. In activated BMMs, the miRNA inhibitors attenuated inhibitory effect of PPARγ agonist (troglitazone or ciglitazone), while replenishing the lack of miRNAs induced by PPARγ deficiency using miRNA mimics caused a decline of inflammatory cytokines. In conclusion, these data suggest that 15d-PGJ2/PPARγ axis regulates BMM activation via promoting miR-27b-3p, miR-181a-1-3p, and miR-326-5p expressions. KEY MESSAGES: 15d-PGJ2 inhibits BMM activation via PPARγ activation. 15d-PGJ2/PPARγ axis promotes expression of miR-27b-3p, miR-181a-1-3p, and miR-326-5p. miR-27b-3p, miR-181a-1-3p, and miR-326-5p have an inhibitory effect on BMM activation via 15d-PGJ2/PPARγ axis.

Invariant natural killer T cells contribute to chronic-plus-binge ethanol-mediated liver injury by promoting hepatic neutrophil infiltration.

Neutrophil infiltration is a hallmark of alcoholic steatohepatitis; however, the underlying mechanisms remain unclear. We previously reported that chronic-plus-binge ethanol feeding synergistically induces hepatic recruitment of neutrophils, which contributes to liver injury. In this paper, we investigated the roles of invariant natural killer T (iNKT) cells in chronic-plus-binge ethanol feeding-induced hepatic neutrophil infiltration and liver injury. Wild-type and two strains of iNKT cell-deficient mice (CD1d- and Jα18-deficient mice) were subjected to chronic-plus-binge ethanol feeding. Liver injury and inflammation were examined. Chronic-plus-binge ethanol feeding synergistically increased the number of hepatic iNKT cells and induced their activation, compared with chronic feeding or binge alone. iNKT cell-deficient mice were protected from chronic-plus-binge ethanol-induced hepatic neutrophil infiltration and liver injury. Moreover, chronic-plus-binge ethanol feeding markedly upregulated the hepatic expression of several genes associated with inflammation and neutrophil recruitment in wild-type mice, but induction of these genes was abrogated in iNKT cell-deficient mice. Importantly, several cytokines and chemokines (e.g., MIP-2, MIP-1, IL-4, IL-6 and osteopontin) involved in neutrophil infiltration were upregulated in hepatic NKT cells isolated from chronic-plus-binge ethanol-fed mice compared to pair-fed mice. Finally, treatment with CD1d blocking antibody, which blocks iNKT cell activation, partially prevented chronic-plus-binge ethanol-induced liver injury and inflammation. Chronic-plus-binge ethanol feeding activates hepatic iNKT cells, which play a critical role in the development of early alcoholic liver injury, in part by releasing mediators that recruit neutrophils to the liver, and thus, iNKT cells represent a potential therapeutic target for the treatment of alcoholic liver disease.

Immunomodulation and liver protection of Yinchenhao decoction against concanavalin A-induced chronic liver injury in mice.

OBJECTIVE: This study investigated the immunoregulatory and protective roles of Yinchenhao decoction, a compound of Chinese herbal medicine, in a mouse model of concanavalin A (ConA)-induced chronic liver injury. METHODS: Female BalB/c mice were randomly divided into 4 groups: normal control, ConA model, ConA model treated with Yinchenhao decoction (400 mg/kg, orally), and ConA model treated with dexamethasone (0.5 mg/kg, orally). All treatments were given once a day for 28 d. Except of the normal control, mice received tail vein injection of ConA (10 mg/kg) on days 7, 14, 21, and 28, at 1 h after treatment with Yinchenhao decoction or dexamethasone or saline to induce chronic liver injury. RESULTS: Repeated ConA injection induced chronic liver injury, which was evidenced by inflammatory cell infiltration and necrosis, increased serum alanine aminotranferease activities, decreased albumin levels, and an imbalanced expression of immunoregulatory genes in the liver tissues including significantly enhanced interferon-γ, interleukin-4, monocyte chemotactic protein-1, and cluster of differentiation 163 mRNA levels, and reduced tumor necrosis factor-α and interleukin-6 mRNA levels. Treatment with Yinchenhao decoction significantly reversed the ConA-induced changes in immunoregulatory gene expression in the liver tissues, reduced serum alanine aminotranferease activity, enhanced serum albumin level, and attenuated the extent of liver inflammation and necrosis. Furthermore, Yinchenhao decoction did not result in hepatocyte degeneration and spleen weight loss that were observed in mice received long-term treatment with dexamethasone. CONCLUSION: Yinchenhao decoction treatment protected liver against the ConA-induced chronic liver damage and improved liver function, which were associated with the modulation of gene expression related to immune/inflammatory response.

[Evaluation of the phagocytic activity and the killing of peripheral blood monocytes in the offspring of female rats with an experimental drug induced liver pathology].

In this study, the functional activity of monocytes of peripheral blood in the offspring of female rats with paracetamol liver disease was investigated. Phagocytic property of these cells and their bactericidal activity was investigated. It is established, that the drug induced liver disease leads to reducing of functional activity of peripheral blood monocytes.

Dexmedetomidine premedication attenuates concanavalin A-induced hepatitis in mice.

Activated T cells selectively induced by concanavalin A (Con A) in liver are subsequent efficient resolution of inflammation. Activated T cells infiltrating in liver combined with pro-inflammatory cytokines are the major causes in Con A-induced liver injury. In our study, C57/BL mice were injected with Con A combined with dexmedetomidine or not. ALT and AST in blood and histopathology of liver were measured. T cell infiltration in liver was examined by flow cytometry and pro-inflammatory cytokines including IL-6, IL-10, TNF-α, and IFN-γ in blood were measured by ELISA. The mRNA level of CXCL10 was detected by RT-PCR and the protein level of NF-κB was measured by Western-blot. We found that dexmedetomidine alleviated Con A-induced liver injury by down-regulating levels of ALT and AST in blood and the severity of histopathology, which reflect the severity of hepatitis induced by Con A. In addition, pro-inflammatory cytokines in blood were attenuated by dexmedetomidine. Dexmedetomidine restrained the phosphorylation of NF-κB IκBα and P-65 dramatically which may participate in the regulation of cytokines secretion. Moreover, CXCL10 mRNA attenuated by dexmedetomidine in liver may result in the lower level of CD4(+) T cells infiltration in liver. These results suggested that dexmedetomidine might be a potential compound in treating T cell-mediated liver injury.

Comparative gene and protein expression analyses of a panel of cytokines in acute and chronic drug-induced liver injury in rats.

Drug-induced liver injury (DILI) is a significant safety issue associated with medication use, and is the major cause of failures in drug development and withdrawal in post marketing. Cytokines are signaling molecules produced and secreted by immune cells and play crucial roles in the progression of DILI. Although there are numerous reports of cytokine changes in several DILI models, a comprehensive analysis of cytokine expression changes in rat liver injury induced by various compounds has, to the best of our knowledge, not been performed. In the past several years, we have built a public, free, large-scale toxicogenomics database, called Open TG-GATEs, containing microarray data and toxicity data of the liver of rats treated with various hepatotoxic compounds. In this study, we measured the protein expression levels of a panel of 24 cytokines in frozen liver of rats treated with a total of 20 compounds, obtained in the original study that formed the basis of the Open TG-GATEs database and analyzed protein expression profiles combined with mRNA expression profiles to investigate the correlation between mRNA and protein expression levels. As a result, we demonstrated significant correlations between mRNA and protein expression changes for interleukin (IL)-1ß, IL-1α, monocyte chemo-attractant protein (MCP)-1/CC-chemokine ligand (Ccl)2, vascular endothelial growth factor A (VEGF-A), and regulated upon activation normal T cell expressed and secreted (RANTES)/Ccl5 in several different types of DILI. We also demonstrated that IL-1ß protein and MCP-1/Ccl2 mRNA were commonly up-regulated in the liver of rats treated with different classes of hepatotoxicants and exhibited the highest accuracy in the detection of hepatotoxicity. The results also demonstrate that hepatic mRNA changes do not always correlate with protein changes of cytokines in the liver. This is the first study to provide a comprehensive analysis of mRNA-protein correlations of factors involved in various types of DILI, as well as additional insights into the importance of understanding complex cytokine expression changes in assessing DILI.

A TLR2/S100A9/CXCL-2 signaling network is necessary for neutrophil recruitment in acute and chronic liver injury in the mouse.

BACKGROUND & AIMS: Neutrophils are important immune effectors required for sterile and non-sterile inflammatory responses. However, neutrophils are associated with pathology in drug-induced liver injury, acute alcoholic liver disease, and ischemia-reperfusion injury. An understanding of the complex mechanisms that control neutrophil recruitment to the injured liver is desirable for developing strategies aimed at limiting neutrophil-mediated cellular damage. METHODS: Wt, tlr2(-/-), tlr4(-/-), and s100a9(-/-) mice were administered CCl4 either acutely (8, 24, 48, or 72 h) or chronically (8 weeks) and livers investigated by histological (IHC for neutrophils, fibrogenesis, proliferation, and chemotactic proteins) or molecular approaches (qRT-PCR for neutrophil chemoattractant chemokines and cytokines as well as pro-fibrogenic genes). RESULTS: Mice lacking TLR2 or S100A9 failed to recruit neutrophils to the injured liver and had a defective hepatic induction of the neutrophil chemokine CXCL-2. Hierarchy between TLR2 and S100A9 proved to be complex. While induction of S100A9 was dependent on TLR2 in isolated neutrophils, there was a more complicated two-way signalling cross-talk between TLR2 and S100A9 in whole liver. However, wound-healing and regenerative responses of the liver were unaffected in these genetic backgrounds as well as in wild type mice, in which neutrophils were depleted by infusion of Ly-6G antibody. CONCLUSIONS: We have identified TLR2 and S100A8/S100A9 as key regulators of hepatic CXCL-2 expression and neutrophil recruitment. This novel TLR2-S100A9-CXCL-2 pathway may be of use in development of new strategies for selectively manipulating neutrophils in liver disease without impairing normal wound healing and regenerative responses.

The role of innate immunity in the pathogenesis of preneoplasia in drug-induced chronic hepatitis based on a mouse model.

Innate immunity factors such as conversion of the 26S proteasome to form the immunoproteasome and the Toll-like receptor signaling pathways are activated in chronic hepatitis induced by the carcinogenic drug DDC. Over time, preneoplastic hepatocyte phenotypes appear in the liver parenchyma. These changed hepatocytes expand in number because they have a growth advantage over normal hepatocytes when responding to chronic liver injury. The changed hepatocytes can be identified using immunofluorescent antibodies to preneoplastic cells e.g. FAT10/UbD, A2 macroglobulin, glutathione transpeptidase, alpha fetoprotein, glycipan 3, FAS, and gamma glutamyl transpeptidase. The formation of the preneoplastic cells occurs concomitant with activation of the Toll-like receptor signaling pathways and the transformation of the 26S proteasome to form the immunoproteasome. This transformation is in response to interferon stimulating response element on the promoter of the FAT10/UbD gene. NFκB, Erk, p38 and Jnk are also up regulated. Specific inhibitors block these responses in vitro in a mouse tumor cell line exposed to interferon gamma. Mallory-Denk bodies form in these preneoplastic cells, because of the depletion of the 26S proteasome due to formation of the immunoproteasome. Thus, MDB forming cells are also markers of the preneoplastic hepatocytes. The UbD positive preneoplastic cells regress when the liver injury induced chronic hepatitis subsides. When the drug DDC is refed to mice and chronic hepatitis is activated, the preneoplastic cell population expands and Mallory-Denk bodies rapidly reform. This response is remembered by the preneoplastic cells for at least four months indicating that an epigenetic cellular memory has formed in the preneoplastic cells. This proliferative response is prevented by feeding methyl donors such as S-adenosylmethionine or betaine. Drug feeding reduces the methylation of H(3) K4, 9, and 27 and this response is prevented by feeding the methyl donors. After 8 to 15months of drug withdrawal in mice the preneoplastic liver cells persist as single or small clusters of cells in the liver lobules. Multiple liver tumors form, some of which are hepatocellular carcinomas. The tumors immunostain positively for the same preneoplastic markers as the preneoplastic cells. Similar cells are identified in human cirrhosis and hepatocellular carcinoma indicating the relevance of the drug model described here to the preneoplastic changes associated with human chronic hepatitis and hepatocellular carcinoma.

Immune-mediated drug-induced liver disease.

Drug-induced immune-mediated hepatic injury is an adverse immune response against the liver that results in a disease with hepatitic, cholestatic, or mixed clinical features. Drugs such as halothane, tienilic acid, dihydralazine, and anticonvulsants trigger a hepatitic reaction, and drugs such as chlorpromazine, erythromycins, amoxicillin-calvulanic acid, sulfonamides and sulindac trigger a cholestatic or mixed reaction. Unstable metabolites derived from the metabolism of the drug may bind to cellular proteins or macromolecules, leading to a direct toxic effect on hepatocytes. Protein adducts formed in the metabolism of the drug may be recognized by the immune system as neoantigens. Immunocyte activation may then generate autoantibodies and cell-mediated immune responses, which in turn damage the hepatocytes. Cytochromes 450 are the major oxidative catalysts in drug metabolism, and they can form a neoantigen by covalently binding with the drug metabolite that they produce. Autoantibodies that develop are selectively directed against the particular cytochrome isoenzyme that metabolized the parent drug. The hapten hypothesis proposes that the drug metabolite can act as a hapten and can modify the self of the individual by covalently binding to proteins. The danger hypothesis proposes that the immune system only responds to a foreign antigen if the antigen is associated with a danger signal, such as cell stress or cell death. Most clinically overt adverse hepatic events associated with drugs are unpredictable, and they have intermediate (1 to 8 weeks) or long latency (up to 12 months) periods characteristic of hypersensitivity reactions. Immune-mediated drug-induced liver disease nearly always disappears or becomes quiescent when the drug is removed. Methyldopa, minocycline, and nitrofurantoin can produce a chronic hepatitis resembling AIH if the drug is continued.

[Possible mechanisms of the reciprocal influence of infections caused by HIV and hepatitis C virus]. / Vozmozhnye mekhanizmy vzaimnogo vliianiia infektsii, vyzyvaemykh VICH i virusom gepatita C.

Literature data on the pathogenesis of mixed infection caused by human immunodeficiency viruses (HIV), type I, and hepatitis C virus (HCV), as well as on possible mechanisms of the reciprocal influence of these viruses necessary to understand their co-existence, are reviewed. The extrahepatic replication of HCV, its role in the infectious process and its possible contribution to the course of mono- and co-infection are considered in detail. Much attention is paid to the specific features of immune response in HIV-HCV infection and the immunomediated mechanisms of the reciprocal influence of the viruses. The problem of the hepatotoxicity of antiretrovirus preparations, actively discussed in literature, is considered from biological positions. The role of the phenomenon of immunity reconstitution in cases of the exacerbation of chronic HCV infection in the course of the treatment of HIV infection as well as of other factors, in particular, infections caused by other parenterally transmitted viruses, in the course of HIV-HCV co-infection is pointed out.

Drug-induced immunotoxicity.

Immune-related drug responses are one of the most common sources of idiosyncratic toxicity. A number of organs may be the target of such reactions; however, this review concentrates mostly on the liver. Drug-induced hepatitis is generally divided into two categories: acute hepatitis in which the drug or a metabolite destroys a vital target in the cell; immunoallergic hepatitis in which the drug triggers an adverse immune response directed against the liver. Their clinical features are: a) low frequency; b) dose independence; c) typical immune system manifestations such as fever, eosinophilia; d) delay between the initiation of treatment and onset of the disease; e) a shortened delay upon rechallenge; and f) occasional presence of autoantibodies in the serum of patients. Such signs have been found in cases of hepatitis triggered by drugs such as halothane, tienilic acid, dihydralazine and anticonvulsants. They will be taken as examples to demonstrate the recent progress made in determining the mechanisms responsible for the disease. The following mechanisms have been postulated: 1) the drug is first metabolized into a reactive metabolite which binds to the enzyme that generated it; 2) this produces a neoantigen which, once presented to the immune system, might trigger an immune response characterized by 3) the production of antibodies recognizing both the native and/or the modified protein; 4) rechallenge leads to increased neoantigen production, a situation in which the presence of antibodies may induce cytolysis. Toxicity is related to the nature and amount of neoantigen and also to other factors such as the individual immune system. An effort should be made to better understand the precise mechanisms underlying this kind of disease and thereby identify the drugs at risk; and also the neoantigen processes necessary for their introduction into the immune system. An animal model would be useful in this regard.