• R01 CA267554 NCI NIH HHS

Several therapies with immune-modulatory functions have been proposed to reduce the overwhelmed inflammation associated with COVID-19. Here we investigated the impact of IL-10 in COVID-19, through the ex-vivo assessment of the effects of exogenous IL-10 on SARS-CoV-2-specific-response using a whole-blood platform.

Two cohorts were evaluated: in “study population A”, plasma levels of 27 immune factors were measured by a multiplex (Luminex) assay in 39 hospitalized “COVID-19 patients” and 29 “NO COVID-19 controls” all unvaccinated. In “study population B”, 29 COVID-19 patients and 30 NO COVID-19-Vaccinated Controls (NO COVID-19-VCs) were prospectively enrolled for the IL-10 study. Whole-blood was stimulated overnight with SARS-COV-2 antigens and then treated with IL-10. Plasma was collected and used for ELISA and multiplex assay. In parallel, whole-blood was stimulated and used for flow cytometry analysis.

Baseline levels of several immune factors, including IL-10, were significantly elevated in COVID-19 patients compared with NO COVID-19 subjects in “study population A”. Among them, IL-2, FGF, IFN-γ, and MCP-1 reached their highest levels within the second week of infection and then decreased. To note that, MCP-1 levels remained significantly elevated compared with controls. IL-10, GM-CSF, and IL-6 increased later and showed an increasing trend over time. Moreover, exogenous addition of IL-10 significantly downregulated IFN-γ response and several other immune factors in both COVID-19 patients and NO COVID-19-VCs evaluated by ELISA and a multiplex analysis (Luminex) in “study population B”. Importantly, IL-10 did not affect cell survival, but decreased the frequencies of T-cells producing IFN-γ, TNF-α, and IL-2 (p<0.05) and down-modulated HLA-DR expression on CD8⁺ and NK cells.

This study provides important insights into immune modulating effects of IL-10 in COVID-19 and may provide valuable information regarding the further in vivo investigations.

• COVID-19
• Granulocyte-Macrophage Colony-Stimulating Factor
• HLA-DR Antigens/analysis
• Humans
• Interleukin-10
• Interleukin-2
• Interleukin-6
• SARS-CoV-2
• Tumor Necrosis Factor-alpha

• HCC
• HCV
• IL-10
• IL-6
• Polymorphism

Liver fibrosis is a result of continuous damage to the liver combined with accumulation of the extracellular matrix and is characteristic of most chronic liver diseases such as hepatitis C virus (HCV) infection.

This study evaluated interleukin 10 (IL10) expression in the liver and plasma of 45 HCV patients and its association with the pathogenesis and progression of liver fibrosis. The expression of transforming growth factor beta (TGFB1) was also assessed. Patients were divided into three groups according to the METAVIR classification (F0-F1, F2 and F3-F4); there was also a control group (n = 8).

In the control group, high intrahepatic IL10 mRNA expression showed a positive association with F0-F1 fibrosis, no inflammation, low concentrations of liver enzymes and a high viral load; conversely, low intrahepatic IL10 mRNA expression showed a negative association with fibrosis progression. Intrahepatic TGFB1 mRNA expression was greater in the HCV group than in the control group, and regarding different disease phases, its expression increased as fibrosis evolved to more severe forms.

Intrahepatic IL10 mRNA expression decreases with persistent fibrosis, probably due to the production of TGF-β1, a potent antimitotic and fibrogenic cytokine. IL10 restricts and decreases the immune response and limits the fibrogenic response; however, a decrease in IL10 favors persistent inflammatory infiltrate, resulting in severe fibrosis.

• Case-Control Studies
• Female
• Hepacivirus/isolation & purification
• Hepatitis C, Chronic/complications
• Hepatitis C, Chronic/virology
• Humans
• Interleukin-10/genetics
• Interleukin-10/metabolism
• Liver/metabolism
• Liver/pathology
• Liver Cirrhosis/etiology
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/pathology
• Male
• Middle Aged
• Transforming Growth Factor beta1/genetics
• Transforming Growth Factor beta1/metabolism
• Viral Load

• Conselho Nacional de Desenvolvimento Científico e Tecnológico
• Universidade Federal do Pará

Chronic hepatitis C is associated with a high risk of developing hepatocellular carcinoma (HCC) because of a direct effect of the Hepatitis C Virus (HCV) proteins and an indirect oncogenic effect of chronic inflammation and impaired immune response. The treatment of chronic hepatitis C markedly reduces all-cause mortality; in fact, interferon-based treatment has shown a reduction of HCC incidence of more than 70%. The recent introduction of the highly effective direct-acting antivirals (DAAs) has completely changed the scenario of chronic hepatitis C (CHC) with rates of HCV cure over 90%. However, an unexpectedly high incidence of HCC recurrence was observed in patients after DAA treatment (27% versus 0.4–2% in patients who received interferon treatment). The mechanism that underlies the high rate of tumor relapse is currently unknown and is one of the main issues in hepatology. We reviewed the possible mechanisms involved in HCC recurrence after DAA treatment.

• direct-acting antivirals
• hepatocellular carcinoma

• Animals
• Antiviral Agents/therapeutic use
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/epidemiology
• Carcinoma, Hepatocellular/immunology
• Carcinoma, Hepatocellular/virology
• Hepacivirus/drug effects
• Hepacivirus/immunology
• Hepatitis C, Chronic/drug therapy
• Hepatitis C, Chronic/epidemiology
• Hepatitis C, Chronic/immunology
• Hepatitis C, Chronic/virology
• Humans
• Incidence
• Interferons/therapeutic use
• Liver Neoplasms/drug therapy
• Liver Neoplasms/epidemiology
• Liver Neoplasms/immunology
• Liver Neoplasms/virology
• Macrophages/drug effects
• Monocytes/drug effects
• Neoplasm Recurrence, Local/drug therapy
• Neoplasm Recurrence, Local/epidemiology
• Neoplasm Recurrence, Local/immunology
• Neoplasm Recurrence, Local/virology
• Neutrophils/drug effects

• HCV
• Liver cirrhosis
• PRI-724
• Wnt inhibitor

• Adult
• Aged
• Bridged Bicyclo Compounds, Heterocyclic/administration & dosage
• Bridged Bicyclo Compounds, Heterocyclic/adverse effects
• Bridged Bicyclo Compounds, Heterocyclic/therapeutic use
• Female
• Genotype
• Hepacivirus/genetics
• Hepatitis C, Chronic/complications
• Hepatitis C, Chronic/diagnosis
• Hepatitis C, Chronic/metabolism
• Hepatitis C, Chronic/virology
• Humans
• Liver Cirrhosis/diagnosis
• Liver Cirrhosis/drug therapy
• Liver Cirrhosis/etiology
• Liver Function Tests
• Male
• Middle Aged
• Pyrimidinones/administration & dosage
• Pyrimidinones/adverse effects
• Pyrimidinones/therapeutic use
• Treatment Outcome
• Viral Load
• beta Catenin/antagonists & inhibitors

• 1-Naphthylisothiocyanate
• Animals
• Bile Acids and Salts/blood
• Bilirubin/metabolism
• Cholestasis/blood
• Cholestasis/chemically induced
• Cholestasis/drug therapy
• Cholestasis/prevention & control
• Cytokines/genetics
• Cytokines/metabolism
• Drugs, Chinese Herbal/therapeutic use
• Gene Expression Regulation
• Inflammation Mediators/metabolism
• Liver/metabolism
• Male
• Protective Agents/therapeutic use
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Rats, Wistar

• Cellular targets
• Combinational therapy
• Hepatocellular carcinoma
• Immunostimulation
• Immunotherapy
• Molecular targets
• Virotherapy

• Adult
• Aged
• Aged, 80 and over
• Antiviral Agents/administration & dosage
• Antiviral Agents/adverse effects
• Cell Proliferation/drug effects
• Epidermal Growth Factor/blood
• Female
• Hepacivirus/metabolism
• Hepatitis C/blood
• Hepatitis C/drug therapy
• Human Umbilical Vein Endothelial Cells/metabolism
• Humans
• Inflammation/blood
• Inflammation/drug therapy
• Interleukin-10/blood
• Male
• Middle Aged
• Neoplasms
• Tumor Necrosis Factor-alpha/blood
• Vascular Endothelial Growth Factor A/blood

• chronic infections
• host–virus interactions
• susceptibility
• treatment

• Carcinoma, Hepatocellular/immunology
• HLA Antigens/genetics
• HLA Antigens/immunology
• Hepacivirus/immunology
• Hepatitis B virus/immunology
• Hepatitis B, Chronic/complications
• Hepatitis B, Chronic/immunology
• Hepatitis C, Chronic/complications
• Hepatitis C, Chronic/immunology
• Humans
• Immunologic Factors/genetics
• Immunologic Factors/immunology
• Interleukins/genetics
• Interleukins/immunology
• Liver Cirrhosis/etiology
• Liver Cirrhosis/immunology
• Liver Neoplasms/immunology
• Mannose-Binding Lectin/genetics
• Mannose-Binding Lectin/immunology
• Polymorphism, Single Nucleotide
• Receptor, Interferon alpha-beta/genetics
• Receptor, Interferon alpha-beta/immunology
• Receptors, CCR5/genetics
• Receptors, CCR5/immunology
• Tumor Necrosis Factor-alpha/genetics
• Tumor Necrosis Factor-alpha/immunology

Interleukin-10 (IL-10) is a multifunctional cytokine that exerts potent context specific immunostimulatory and immunosuppressive effects. We have investigated the mechanism by which PEGylated rIL-10 regulates plasma cholesterol in mice and humans. In agreement with previous work on rIL-10, we report that PEGylated rIL-10 harnesses the myeloid immune system to control total plasma cholesterol levels. We have discovered that PEG-rMuIL-10’s dramatic lowering of plasma cholesterol is dependent on phagocytotic cells. In particular, PEG-rHuIL-10 enhances cholesterol uptake by Kupffer cells. In addition, removal of phagocytotic cells dramatically increases plasma cholesterol levels, suggesting for the first time that immunological cells are implicitly involved in regulating total cholesterol levels. These data suggest that treatment with PEG-rIL-10 potentiates endogenous cholesterol regulating cell populations not currently targeted by standard of care therapeutics. Furthermore, we show that IL-10’s increase of Kupffer cell cholesterol phagocytosis is concomitant with decreases in liver cholesterol and triglycerides. This leads to the reversal of early periportal liver fibrosis and facilitates the restoration of liver health. These data recommend PEG-rIL-10 for evaluation in the treatment of fatty liver disease and preventing its progression to non-alcoholic steatohepatitis. In direct confirmation of our in vivo findings in the treatment of hypercholesterolemic mice with PEG-rMuIL-10, we report that treatment of hypercholesterolemic cancer patients with PEG-rHuIL-10 lowers total plasma cholesterol by up to 50%. Taken together these data suggest that PEG-rIL-10’s cholesterol regulating biology is consistent between mice and humans.

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Animals
• Cholesterol/blood
• Cholesterol/immunology
• Female
• Humans
• Hypercholesterolemia/blood
• Hypercholesterolemia/drug therapy
• Hypercholesterolemia/immunology
• Immunologic Factors/chemistry
• Immunologic Factors/pharmacology
• Immunologic Factors/therapeutic use
• Interleukin-10/chemistry
• Interleukin-10/pharmacology
• Interleukin-10/therapeutic use
• Kupffer Cells/drug effects
• Kupffer Cells/immunology
• Male
• Mice, Inbred C57BL
• Middle Aged
• Phagocytosis/drug effects
• Polyethylene Glycols/chemistry
• Polyethylene Glycols/pharmacology
• Polyethylene Glycols/therapeutic use
• Recombinant Proteins/chemistry
• Recombinant Proteins/pharmacology
• Recombinant Proteins/therapeutic use
• Young Adult

Importance of chronic fibroproliferative diseases (FDs) including pulmonary fibrosis, chronic kidney diseases, inflammatory bowel disease, and cardiovascular or liver fibrosis is rapidly increasing and they have become a major public health problem. According to some estimates about 45% of all deaths are attributed to FDs in the developed world. Independently of their etiology the common hallmark of FDs is chronic inflammation. Infiltrating immune cells, endothelial, epithelial, and other resident cells of the injured organ release an orchestra of inflammatory mediators, which stimulate the proliferation and excessive extracellular matrix (ECM) production of myofibroblasts, the effector cells of organ fibrosis. Abnormal amount of ECM disturbs the original organ architecture leading to the decline of function. Although our knowledge is rapidly expanding, we still have neither a diagnostic tool to detect nor a drug to specifically target fibrosis. Therefore, there is an urgent need for the more comprehensive understanding of the pathomechanism of fibrosis and development of novel diagnostic and therapeutic strategies. In the present review we provide an overview of the common key mediators of organ fibrosis highlighting the role of interleukin-10 (IL-10) cytokine family members (IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26), which recently came into focus as tissue remodeling-related inflammatory cytokines.

Progressive liver fibrosis is a major health issue for which no effective treatment is available, leading to cirrhosis and orthotopic liver transplantation. However, organ shortage is a reality. Hence, there is an urgent need to find alternative therapeutic strategies. Cell-based therapy using mesenchymal stem cells (MSCs) may represent an attractive therapeutic option, based on their immunomodulatory properties, their potential to differentiate into hepatocytes, allowing the replacement of damaged hepatocytes, their potential to promote residual hepatocytes regeneration and their capacity to inhibit hepatic stellate cell activation or induce their apoptosis, particularly via paracrine mechanisms. The current review will highlight recent findings regarding the input of MSC-based therapy for the treatment of liver fibrosis, from in vitro studies to pre-clinical and clinical trials. Several studies have shown the ability of MSCs to reduce liver fibrosis and improve liver function. However, despite these promising results, some limitations need to be considered. Future prospects will also be discussed in this review.

• Liver fibrosis
• Cirrhosis
• Mesenchymal stem cells
• Cell therapy
• Hepatic stellate cells

• Animals
• Cell Differentiation
• Cell Proliferation
• Cell Survival
• Graft Survival
• Humans
• Liver/metabolism
• Liver/pathology
• Liver/physiopathology
• Liver/surgery
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/pathology
• Liver Cirrhosis/physiopathology
• Liver Cirrhosis/surgery
• Liver Regeneration
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/metabolism
• Regenerative Medicine/methods
• Treatment Outcome

• Nanomedicine
• liposomes
• liver disease
• liver fibrosis
• liver inflammation
• nanoparticles
• nanotheranostics

• Chronic Hepatitis B
• Chronic Liver Failure
• Cytokines
• Interleukin-10
• Severe Exacerbation

• Aged
• Alanine Transaminase/blood
• Female
• Genetic Association Studies
• Hepatitis C, Chronic/blood
• Hepatitis C, Chronic/genetics
• Humans
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Receptor, Cannabinoid, CB2/genetics

• HCV genotype 4
• chronic hepatitis C
• interleukin-10
• resolved hepatitis C
• single nucleotide polymorphism

Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the United-States. The aim of the study was to describe serum immune profiles associated with acute DILI, to investigate whether there are profiles associated with clinical features or types of DILI and/or with prognosis, and to assess temporal changes in levels. Twenty-seven immune analytes were measured in the sera of 78 DILI subjects in the Drug-Induced Liver Injury Network (DILIN) and compared with 40 healthy controls. Immune analytes (14 cytokines, 7 chemokines and 6 growth factors) were measured by BioPlex multiplex ELISA at DILI onset and after 6 months. A modeling process utilizing immune principles was used to select a final set of variables among 27 immune analytes and several additional clinical lab values for prediction of early death (within 6 months of DILI onset). Nineteen of the 27 immune analytes were differentially expressed among healthy control, DILI onset and 6-month cohorts. Disparate patterns of immune responses, especially innate and adaptive cellular (mostly TH17) immunity were evident. Low values of four immune analytes (IL-9, IL-17, PDGF-bb and RANTES) and serum albumin are predictive of early death [PPV = 88% (95% CI, 65%-100%), NPV = 97% (95% CI, 93%-100%), accuracy = 96% (95% CI, 92%-100%)].

The current standard of care (SOC) for hepatitis C virus (HCV) infection is the combination of pegylated interferon (PEG-IFN), Ribavirin and protease inhibitor for HCV genotype 1. Nevertheless, this treatment is successful only in 70-80% of the patients. In addition, the treatment is not economical and is of immense physical burden for the subject. It has been established now, that virus-host interactions play a significant role in determining treatment outcomes. Therefore identifying biological markers that may predict the treatment response and hence treatment outcome would be useful. Both IFN and Ribavirin mainly act by modulating the immune system of the patient. Therefore, the treatment response is influenced by genetic variations of the human as well as the HCV genome. The goal of this review article is to summarize the impact of recent scientific advances in this area regarding the understanding of human and HCV genetic variations and their effect on treatment outcomes. Google scholar and PubMed have been used for literature research. Among the host factors, the most prominent associations are polymorphisms within the region of the interleukin 28B (IL28B) gene, but variations in other cytokine genes have also been linked with the treatment outcome. Among the viral factors, HCV genotypes are noteworthy. Moreover, for sustained virological responses (SVR), variations in core, p7, non-structural 2 (NS2), NS3 and NS5A genes are also important. However, all considered single nucleotide polymorphisms (SNPs) of IL28B and viral genotypes are the most important predictors for interferon based therapy of HCV infection.

• fibrosis
• cytokine
• macrophage
• fibroblast
• myofibroblast
• inflammation

• Cytokines
• Fibrosis
• Humans
• Inflammation
• Skin
• Wound Healing

• G0700861 Medical Research Council
• ZIA AI000829-15 Intramural NIH HHS
• ZIA AI001019-06 Intramural NIH HHS

• Antiviral Agents/therapeutic use
• Biopsy
• Disease Progression
• Elasticity Imaging Techniques
• Hepatitis C/complications
• Hepatitis C/prevention & control
• Hepatitis C/surgery
• Humans
• Liver/pathology
• Liver Cirrhosis/diagnosis
• Liver Cirrhosis/therapy
• Liver Transplantation
• Prognosis
• Recurrence

• Animals
• Apoptosis
• Biomarkers/metabolism
• Disease Progression
• Fibrosis
• Hepatic Stellate Cells/cytology
• Hepatocytes/cytology
• Humans
• Inflammation
• Liver/injuries
• Liver Cirrhosis/pathology
• Liver Cirrhosis/therapy
• Liver Diseases
• Macrophages/cytology
• Mice
• Monocytes/cytology
• Myofibroblasts/cytology
• Stem Cells/cytology
• T-Lymphocytes/cytology
• Wound Healing

• treg
• il-17
• mmp-1
• liver fibrosis

Hepatitis C virus infection is a major cause of chronic liver disease. CD4⁺ T cells play a key role in disease outcome. However, the critical functions and associated phenotypes of intrahepatic CD4⁺ T cells are not well defined. We have previously shown that CD8⁺ T cells expressing the C type lectin CD161 are highly enriched in the human liver, especially during chronic hepatitis. These cells are associated with a type 17 differentiation pattern and express cytokines including IL-17A, IL-22, and IFN-γ. We therefore analyzed expression of CD161 on CD4⁺ T cells in blood and liver and addressed the relevant phenotype and functional capacity of these populations. We observed marked enrichment of CD161⁺CD4⁺ T cells in the liver during chronic hepatitis such that they are the dominant subtype (mean 55% of CD4⁺ T cells). IL-22 and IL-17 secreting CD4⁺ T cells were readily found in the livers of HCV⁺ and NASH donors, although not enriched compared to blood. There was, however, specific enrichment of a novel subset of IL-22/IFN-γ dual secretors (p = 0.02) compared to blood, a result reconfirmed with direct ex vivo analyses. These data indicate the dominance of CD161⁺ expressing lymphocyte populations within the hepatic infiltrate, associated with a distinct cytokine profile. Given their documented roles as antiviral and hepatoprotective cytokines respectively, the impact of co-secretion of IFN-γ and IL-22 in the liver may be particularly significant.

• CD161
• CD4+ T cell
• HCV
• IL-22
• hepatic inflammation

Alcohol related costs to health and society are high. One of the most serious complications of alcohol misuse to the individual is the development of alcoholic hepatitis (AH), a clinical syndrome of jaundice and progressive inflammatory liver injury in patients with a history of recent heavy alcohol use. It has a poor outcome and few existing successful therapies. The use of glucocorticoids in patients with severe AH is still controversial and there remains a group of patients with glucocorticoid-resistant disease. However, as our understanding of the pathogenesis of the condition improves there are opportunities to develop new targeted therapies with specific actions to control liver inflammation without having a detrimental effect on the immune system as a whole. In this article we review the molecular mechanisms of AH concentrating on the activation of the innate and adaptive immune response. We consider existing treatments including glucocorticoids, anti-tumor necrosis factor therapy and pentoxifylline and their limitations. Using our knowledge of the disease pathogenesis we discuss possible novel therapeutic approaches. New targets include pro-inflammatory cytokines such as interleukin (IL)-17, chemokines and their receptors (for example IL-8, CXCL9 and CXCR3) and augmentation of anti-inflammatory molecules such as IL-10 and IL-22. And there is also future potential to consider combination therapy to selectively modulate the immune response and gain control of disease.

• Alcoholic hepatitis
• Tumour necrosis factor-α
• Pentoxifylline
• Interleukins
• Chemokine receptors

• cirrhosis
• clinical trials
• fibrosis
• hepatic stellate cell
• non-invasive fibrosis assessment

AIM: To assess the association between Interleukin-10 (IL-10) gene IL-10-1082 (G/A), IL-10-592(C/A), IL-10-819 (T/C) polymorphisms and hepatocellular carcinoma (HCC) susceptibility.

METHODS: Two investigators independently searched the Medline, Embase, China National Knowledge Infrastructure, and Chinese Biomedicine Database. Summary odds ratios (ORs) and 95% confidence intervals (95% CIs) for IL-10 polymorphisms and HCC were calculated in a fixed-effects model (the Mantel-Haenszel method) and a random-effects model (the DerSimonian and Laird method) when appropriate.

RESULTS: This meta-analysis included seven eligible studies, which included 1012 HCC cases and 2308 controls. Overall, IL-10-1082 G/A polymorphism was not associated with the risk of HCC (AA vs AG + GG, OR = 1.11, 95% CI = 0.90-1.37). When stratifying for ethnicity, the results were similar (Asian, OR = 1.12, 95% CI = 0.87-1.44; non-Asian, OR = 1.10, 95% CI = 0.75-1.60). In the overall analysis, the IL-10 polymorphism at position -592 (C/A) was identified as a genetic risk factor for HCC among Asians; patients carrying the IL-10-592*C allele had an increased risk of HCC (OR = 1.29, 95% CI = 1.12-1.49). No association was observed between the IL-10-819 T/C polymorphism and HCC susceptibility (TT vs TC + CC, OR = 1.02, 95% CI = 0.79-1.32).

CONCLUSION: This meta-analysis suggests that IL-10-592 A/C polymorphism may be associated with HCC among Asians. IL-10-1082 G/A and IL-10-819 T/C polymorphisms were not detected to be related to the risk for HCC.

• Hepatocellular carcinoma
• Interleukin-10
• Gene polymorphism
• Meta-analysis

• Adenoviridae/genetics
• Animals
• CD4-Positive T-Lymphocytes/immunology
• CD4-Positive T-Lymphocytes/metabolism
• CD8-Positive T-Lymphocytes/immunology
• CD8-Positive T-Lymphocytes/metabolism
• Enzyme-Linked Immunosorbent Assay
• Factor IX
• Flow Cytometry
• Forkhead Transcription Factors/genetics
• Forkhead Transcription Factors/metabolism
• Genetic Vectors/genetics
• Hepatocytes/metabolism
• Humans
• Interferon-gamma/metabolism
• Interleukin-10/genetics
• Interleukin-10/metabolism
• Interleukin-2 Receptor alpha Subunit/genetics
• Interleukin-2 Receptor alpha Subunit/metabolism
• Liver/metabolism
• Male
• Mice
• T-Lymphocytes, Regulatory/immunology
• T-Lymphocytes, Regulatory/metabolism
• Transforming Growth Factor beta/antagonists & inhibitors
• Transforming Growth Factor beta/metabolism

• R01 AI51390 NIAID NIH HHS
• R01 AI051390 NIAID NIH HHS
• P01HL078810 NHLBI NIH HHS
• T32AI007110-27 NIAID NIH HHS
• T32 AI007110 NIAID NIH HHS
• P01 HL078810 NHLBI NIH HHS

Animal experiments using single organs as models of fibrosis spur therapeutic development toward promising targets, but testing of these therapies in human fibrosis yielded disappointing results and limited efficacy. Finding core pathways relevant in different organs that can become fibrotic will uncover molecules that will prove useful as therapeutic targets in many species, including humans. In ‘Bench to Bedside’, Scott Friedman, Wajahat Mehal and John Iredale discuss this new paradigm in fibrosis research and its potential as a new drug development approach. In ‘Bedside to Bench’, Alison Eddy peruses how the protein encoded by UMOD , a gene linked to variable risk for chronic kidney disease and hypertension in humans, may have a role in fibrosis and kidney disease. Uncovering the normal function of UMOD and its gene variants will shed light on the pathogenesis of chronic kidney disease and aid in the discovery of new targets for kidney fibrosis and hypertension.

• Animals
• Disease Models, Animal
• Fibrosis/etiology
• Fibrosis/genetics
• Fibrosis/physiopathology
• Humans
• Mice
• Models, Biological
• Signal Transduction
• Translational Research, Biomedical
• Uromodulin/genetics
• Uromodulin/physiology

• G0600033 Medical Research Council
• R01 DK076674 NIDDK NIH HHS

The Epstein-Barr virus (EBV) has an important and multifaceted role in liver pathology. As a member of the herpes virus family, EBV establishes a persistent infection in more than 90% of adults. Besides acute hepatitis during primary infection, many clinical syndromes of interest for the hepatologist are associated with EBV infection. The role of EBV in the evolution of chronic hepatitis from hepatotropic viruses is considered. Chronic EBV-associated hepatitis is suspected in immunocompetent adults with compatible serology, suggestive histology and detection of the viral genome in the liver and/or increase of specific circulating cytotoxic T-lymphocytes. EBV is the main cause of post-transplant lymphoproliferative disorders which occur in up to 30% of cases. EBV-driven lymphoproliferative diseases are also recognized in non-immunocompromised patients and liver is involved in up to a third of the cases. Directly implicated in the pathogenesis of different tumors, EBV has a disputable role in hepatocellular carcinoma carcinogenesis. Further research is required in order to establish or reject the role of EBV in human liver cancer. This paper attempts to discuss the range of EBV-associated chronic liver diseases in immunocompetent patients, from mild, self-limiting mononuclear hepatitis to liver cancer.

• Epstein-Barr virus
• Chronic hepatitis
• Liver disease
• Chronic active Epstein-Barr virus
• Post-transplant lymphoproliferative disorder
• Infectious mononucleosis

AIM: To investigate the efficacy of Viusid, a nutritional supplement, as an antioxidant and an immunomodulator in patients with chronic hepatitis C.

METHODS: Sixty patients with chronic hepatitis C who were non-responders to standard antiviral treatment were randomly assigned to receive Viusid (3 sachets daily, n = 30) or placebo (n = 30) for 24 wk. The primary outcome was the change in serum malondialdehyde and 4-hydroxyalkenals (lipid peroxidation products). Secondary outcomes were changes in serum tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and interleukin-10 (IL-10).

RESULTS: Statistically significant reductions in serum 4-hydroxyalkenals and malondialdehyde levels were observed in both groups in comparison with pretreatment values, but the patients who received Viusid showed a more marked reduction as compared with the control group (P = 0.001). TNF-α levels significantly increased from 6.9 to 16.2 pg/mL (P < 0.01) in the patients who received placebo in comparison with almost unchanged levels, from 6.6 to 7.1 pg/mL (P = 0.26), in the patients treated with Viusid (P = 0.001). In addition, IL-10 levels were markedly increased in the patients treated with Viusid (from 2.6 to 8.3 pg/mL, P = 0.04) in contrast to the patients assigned to placebo (from 2.8 to 4.1 pg/mL, P = 0.09) (P = 0.01). Likewise, the administration of Viusid markedly increased mean IFN-γ levels from 1.92 to 2.89 pg/mL (P < 0.001) in comparison with a reduction in mean levels from 1.80 to 1.68 pg/mL (P = 0.70) in the placebo group (P < 0.0001). Viusid administration was well tolerated.

CONCLUSION: Our results indicate that treatment with Viusid leads to a notable improvement of oxidative stress and immunological parameters in patients with chronic hepatitis C.

• Antioxidant therapy
• Chronic hepatitis C
• Cytokines
• Immunomodulatory therapy
• Nutritional supplement
• Oxidative stress

• Antigens, CD/biosynthesis
• Antigens, CD/physiology
• B7-H1 Antigen
• CD4-Positive T-Lymphocytes/immunology
• CD4-Positive T-Lymphocytes/physiology
• CD4-Positive T-Lymphocytes/virology
• HIV Infections/immunology
• HIV Infections/physiopathology
• Humans
• Interleukin-10/biosynthesis
• Interleukin-10/physiology
• Lymphocyte Activation/immunology
• Lymphocyte Activation/physiology
• Lymphocyte Subsets/immunology
• Lymphocyte Subsets/physiology
• Monocytes/immunology
• Monocytes/physiology
• Phosphorylation
• Receptors, IgG/immunology
• Receptors, IgG/physiology
• STAT3 Transcription Factor/immunology
• STAT3 Transcription Factor/physiology
• Up-Regulation/physiology
• Viremia/immunology
• Viremia/physiopathology

• P01 AI076174 NIAID NIH HHS

Congenital hepatic fibrosis (CHF) is an autosomal recessive inherited malformation defined pathologically by a variable degree of periportal fibrosis and irregularly shaped proliferating bile ducts. It is one of the fibropolycystic diseases, which also include Caroli disease, autosomal dominant polycystic kidney disease, and autosomal recessive polycystic kidney disease. Clinically it is characterized by hepatic fibrosis, portal hypertension, and renal cystic disease. CHF is known to occur in association with a range of both inherited and non-inherited disorders, with multiorgan involvement, as a result of ductal plate malformation. Because of the similarities in the clinical picture, it is necessary to differentiate CHF from idiopathic portal hypertension and early liver cirrhosis, for which a liver biopsy is essential. Radiological tests are important for recognizing involvement of other organ systems. With regards to our experience at Hacettepe University, a total of 26 patients have been diagnosed and followed-up between 1974 and 2009 with a diagnosis of CHF. Presentation with Caroli syndrome was the most common diagnosis, with all such patients presenting with symptoms of recurrent cholangitis and symptoms related to portal hypertension. Although portal fibrosis is known to contribute to the ensuing portal hypertension, it is our belief that portal vein cavernous transformation also plays an important role in its pathogenesis. In all patients with CHF portal vein morphology should be evaluated by all means since portal vein involvement results in more severe and complicated portal hypertension. Other associations include the Joubert and Bardet-Biedl syndromes.

• Congenital hepatic fibrosis
• Fibropolycystic disorders
• Portal hypertension
• Bardet Biedl syndrome

• soluble il-2 receptor alpha chain (sil-2ra)
• il-2 signaling
• t cell immunosuppression
• liver cancer
• serum
• soluble factors
• tumor tolerance