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Research Interests: Microbiology, Immunology, Medical Microbiology, Natural History, Medicine, and 15 moreHepatitis C, Humans, Hepatitis C Virus, Liver Transplantation, Antimicrobial chemotherapy, Recurrence, Clinical Sciences, Disease Progression, Cirrhosis, Liver Failure, Liver Disease, End Stage Liver Disease, Reoperation, Antiviral Therapy, and Pharmacology and pharmaceutical sciences
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Cells respond to tumour necrosis factor-α (TNF-α) via binding to 75-kDa (type A) and 55-kDa (type B) receptors which have different intracellular signalling pathways and can also circulate as soluble molecules. Both receptors are... more
Cells respond to tumour necrosis factor-α (TNF-α) via binding to 75-kDa (type A) and 55-kDa (type B) receptors which have different intracellular signalling pathways and can also circulate as soluble molecules. Both receptors are co-expressed in many tissues, but their relative contributions to cellular TNF responses is for most situations unknown.In patients with viral and non-viral inflammatory liver diseases serum
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Die Zulassung neuer, direkt antiviral wirkender Substanzen hat die Therapie der Hepatitis C in den letzten zwei Jahren revolutioniert. Eine dauerhafte Viruselimination und damit eine Ausheilung der Hepatitis ist je nach Genotyp,... more
Die Zulassung neuer, direkt antiviral wirkender Substanzen hat die Therapie der Hepatitis C in den letzten zwei Jahren revolutioniert. Eine dauerhafte Viruselimination und damit eine Ausheilung der Hepatitis ist je nach Genotyp, Vorbehandlung und Fibrosestadium bei mehr als 90% der Patienten möglich. Die Therapiedauer hat sich wesentlich verkürzt. Die Nebenwirkungen sind gering (gelegentlich Kopfschmerzen, Übelkeit, Müdigkeit, Durchfälle) und führen nur sehr selten zum Therapieabbruch. Insgesamt hat sich damit die Lage Betroffener deutlich gebessert.
Research Interests: Medicine and Gynecology
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Overcoming hepatitis B virus infection essentially depends on the appropriate immune response of the infected host. Among the hepatitis B virus antigens, the core (HBcAg) and e (HBeAg) proteins appear highly immunogenic and induce... more
Overcoming hepatitis B virus infection essentially depends on the appropriate immune response of the infected host. Among the hepatitis B virus antigens, the core (HBcAg) and e (HBeAg) proteins appear highly immunogenic and induce important lymphocyte effector functions. In order to investigate the importance of HBcAg/HBeAg-specific T lymphocytes in patients with acute and chronic hepatitis B and to identify immunodominant epitopes within the HBcAg/HBeAg, CD4+ T-cell responses to hepatitis B virus-encoded HBcAg and HBcAg/HBeAg-derived peptides were studied in 49 patients with acute and 39 patients with chronic hepatitis B. The results show a frequent antigen-specific CD4+ T-cell activation during acute hepatitis B infection, a rare HBcAg/HBeAg-specific CD4+ T-cell response among HBeAg+ chronic carriers, and no response in patients with anti-HBe+ chronic hepatitis. An increasing CD4+ T-cell response to HBcAg/HBeAg coincides with loss of HBeAg and hepatitis B virus surface antigen (HB...
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Research Interests: Gastroenterology, Medicine, Hepatitis C, Multidisciplinary, Humans, and 15 moreFemale, Male, Hepatitis C Virus, Clinical Sciences, Middle Aged, Genotype, Adult, Combination drug therapy, Ns, Benzimidazoles, Neurosciences, Antiviral Agents, Hepacivirus, Paediatrics and reproductive medicine, and Pharmacology and pharmaceutical sciences
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Since the hepatitis B virus is noncytopathic, it is generally believed that the individual specific immune response determines the course of infection. The lack of data about hepatitis B virus-specific T-cell reactions in acute infection... more
Since the hepatitis B virus is noncytopathic, it is generally believed that the individual specific immune response determines the course of infection. The lack of data about hepatitis B virus-specific T-cell reactions in acute infection led us to investigate the specific cellular immune response of infected individuals in terms of proliferation, and gamma-interferon and lymphotoxin production. Our results demonstrate that peripheral blood mononuclear cells (PBMNC) from patients with acute and chronic hepatitis B respond weakly to HBsAg. In contrast, patients with acute hepatitis show a vigorous response to the nucleocapsid antigen (HBcAg) in terms of proliferation and lymphokine production, while only few chronic virus carriers gave a proliferative response. Either of the antigens could activate lymphocytes to produce gamma-interferon and lymphotoxin, cytokines which may modulate antiviral immune response.
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Research Interests: Virology, Medicine, Hepatitis C, Hepatology, Clinical Sciences, and 4 moreImmune system, CTL, Ns, and epitope
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Research Interests: Immunology, Biology, Histology, Infectious Diseases, Hepatitis C, and 15 moreBiopsy, Biological Sciences, Cell line, Humans, Liver, Female, Hepatitis C Virus, Infectious, Genotype, Graft Rejection, Enzyme Linked Immunosorbent Assay, Antigen, Interferon gamma, Hepacivirus, and Cell culture techniques
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Background/Aims: Pulmonary side effects of interferon-α therapy of chronic hepatitis C seem to be rare. So far, only two cases of sarcoidosis in association with interferon-α treatment of chronic hepatitis C have been... more
Background/Aims: Pulmonary side effects of interferon-α therapy of chronic hepatitis C seem to be rare. So far, only two cases of sarcoidosis in association with interferon-α treatment of chronic hepatitis C have been described.Methods/Cases: We report on three patients who were treated with recombinant interferon-α2a for chronic hepatitis C, two of them in combination with ribavirin. These patients developed pulmonary
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Zusammenfassung Eine 67-jährige depressive Patientin wird mit Vigilanzminderung und Hyponatriämie (105 mmol/l) aufgenommen. Als Ursache der symptomatischen Hyponatriämie findet sich ein Syndrom der inadäquaten ADH-Sekretion (SIADH) unter... more
Zusammenfassung Eine 67-jährige depressive Patientin wird mit Vigilanzminderung und Hyponatriämie (105 mmol/l) aufgenommen. Als Ursache der symptomatischen Hyponatriämie findet sich ein Syndrom der inadäquaten ADH-Sekretion (SIADH) unter Einnahme des selektiven Serotonin-Reuptake-Inhibitors (SSRI) Citalopram. Die Citalopram-Medikation wurde abgesetzt und die Hyponatriämie durch Flüssigkeitsrestriktion und Diuretikagabe langsam ausgeglichen. Angesichts des zunehmenden Einsatzes von SSRIs bei depressiven Patienten werden die Risikofaktoren dieser seltenen, jedoch potenziell
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Research Interests: Clinical Trial, Biology, Adolescent, Medicine, Hepatitis C, and 15 moreBiological Sciences, Humans, Female, Epitope mapping, Male, Antigen Presentation, Hepatitis C Virus, Adult, Amino Acid Sequence, chronic hepatitis C, Hepacivirus, alleles, Human leukocyte antigen, epitope, and Medical and Health Sciences
Virus-specific CD4(+) T-cell response at the site of inflammation is believed to play a decisive role for the course of viral disease. In hepatitis C virus (HCV) infection, the majority of studies focused on the peripheral blood T-cell... more
Virus-specific CD4(+) T-cell response at the site of inflammation is believed to play a decisive role for the course of viral disease. In hepatitis C virus (HCV) infection, the majority of studies focused on the peripheral blood T-cell response. In this study we analyzed intrahepatic virus-specific CD4(+) T-cell response and compared this with that in the peripheral blood. Liver and blood-derived T-cell lines were studied in 36 patients (18 with chronic hepatitis C and 18 with HCV-associated cirrhosis). Virus-specific interferon gamma (IFN-gamma) production at a single cell level to various HCV-proteins (core, nonstructural [NS] 3/4, NS5) were determined by enzyme-linked immunospot (ELIspot). Phenotyping was done by fluorescent-activated cell sorter analysis. In approximately half (16 of 36 [44%]) of intrahepatic T-cell lines a significant number of IFN-gamma spots were observed, whereas this was the case in only 19% (7 of 36 T-cell lines) in the blood. In relative terms, core and nonstructural proteins were recognized with the same frequency in both compartments, but HCV-specificity was significantly more often detected in liver tissue compared with the blood. Hepatitis activity index, viral load, and alanine transaminase levels did not correlate with the detection of HCV-specific CD4(+) T cells. All T-cell lines were dominated by CD4(+) T cells. In conclusion, HCV-specific CD4(+) T cells are multispecific, compartmentalize to the liver, and produce IFN-gamma. We speculate that our data would support the concept of compartmentalization of specific T cells at the site of inflammation and that a low frequency of specific T cells is associated with failure to clear the virus and a chronic course of disease.
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Despite the availability of highly effective and well-tolerated direct-acting antivirals, not all patients with chronic hepatitis C virus infection receive treatment. This retrospective, multi-centre, noninterventional, case-control study... more
Despite the availability of highly effective and well-tolerated direct-acting antivirals, not all patients with chronic hepatitis C virus infection receive treatment. This retrospective, multi-centre, noninterventional, case-control study identified patients with chronic hepatitis C virus infection initiating (control) or not initiating (case) treatment at 43 sites in Germany from September 2017 to June 2018. It aimed to compare characteristics of the two patient populations and to identify factors involved in patient/physician decision to initiate/not initiate chronic hepatitis C virus treatment, with a particular focus on historical barriers. Overall, 793 patients were identified: 573 (72%) who received treatment and 220 (28%) who did not. In 42% of patients, the reason for not initiating treatment was patient wish, particularly due to fear of treatment (17%) or adverse events (13%). Other frequently observed reasons for not initiating treatment were in accordance with known histo...
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Recurrent hepatitis C virus infection after liver transplantation: natural course, therapeutic approach and possible
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Recurrence of hepatitis C virus during leucocytopenia and spontaneous clearance after recovery from cytopenia: a case report
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T cells are believed to be the main players in antiviral defence. To investigate the role of the specific CD4+ T cell response for clearance and control of the hepatitis C virus we studied patients with acute hepatitis C (AHC) during the... more
T cells are believed to be the main players in antiviral defence. To investigate the role of the specific CD4+ T cell response for clearance and control of the hepatitis C virus we studied patients with acute hepatitis C (AHC) during the phase of spontaneous viral clearance and during follow up after elimination of the virus and resolution of disease. Symptomatic AHC has a self‐limited course in 50% of patients, whereas the other half show virus persistence and develop chronic course of disease. Patients who were able to mount a vigorous, polyclonal, multispecific, TH1 lymphokine dominated CD4+ T‐cell response showed viral clearance and a self‐limited course of disease. In contrast, absence of this T‐cell response in patients with AHC invariably led to viral persistence and chronic hepatitis. The characteristics of the T‐cell response were as follows: it was mainly directed against nonstructural proteins of the virus, it was multispecific and demonstrated immunodominant epitopes, an...
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Research Interests: Genetics, Biology, Virology, Hepatology, Mutation, and 3 moreInterferon, Clinical Sciences, and stop codon
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The impacts of viral load, genotype, age, sex and BMI on the clinical course of acute hepatitis C are poorly defined. Here we studied 259 patients with acute HCV infection recruited in the German Hep-Net data base between 1998 and 2008.... more
The impacts of viral load, genotype, age, sex and BMI on the clinical course of acute hepatitis C are poorly defined. Here we studied 259 patients with acute HCV infection recruited in the German Hep-Net data base between 1998 and 2008. Antiviral treatment with interferon alpha was initiated in 171 patients (66 %) within 4 months after the diagnosis of acute hepatitis C. In this cohort (i) the mode of infection was associated with age as iv-drug users were significantly younger than non-iv-drug users while the proportion of patients who acquired HCV by medical procedures increased with age; (ii) patients younger than 30 years were more often infected with genotype 3 (26 % versus 8 % for patients older than 50 years; p = 0.03); (iii) 51 % of patients were icteric and 28 % presented with a 30-fold elevation of liver enzymes, however, no fulminant hepatic failure occurred; (iv) HCV genotype was not associated with disease severity and time to onset of symptoms; (v) low HCV viremia was associated with lower serum AST levels and a longer time from exposure to onset of symptoms; (vi) disease severity was independent from the mode of infection, age, sex and body mass index (BMI). In this large cohort of patients admitted for antiviral therapy, acute hepatitis C took a rather mild course of disease in the majority of patients. Disease severity was not associated with HCV genotype, viral load, age, sex and BMI.
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CD41 T cells play a major role in the host defense against viruses and intracellular microbes. During the natural course of such an infection, specific CD41 T cells are exposed to a wide range of antigen concentrations depending on the... more
CD41 T cells play a major role in the host defense against viruses and intracellular microbes. During the natural course of such an infection, specific CD41 T cells are exposed to a wide range of antigen concentrations depending on the body compartment and the stage of disease. While epitope variants trigger only subsets of T-cell effector functions, the response of virus-specific CD41 T cells to various concentrations of the wild-type antigen has not been systematically studied. We stimulated hepatitis B virus core- and hepatitis C virus NS3-specific CD41 T-cell clones which had been isolated from patients with acute hepatitis during viral clearance with a wide range of specific antigen concentrations and determined the phenotypic changes and the
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Patients who are chronically infected with hepatitis C virus (HCV) and who do not have a sustained virologic response after treatment with regimens containing direct-acting antiviral agents (DAAs) have limited retreatment options. We... more
Patients who are chronically infected with hepatitis C virus (HCV) and who do not have a sustained virologic response after treatment with regimens containing direct-acting antiviral agents (DAAs) have limited retreatment options. We conducted two phase 3 trials involving patients who had been previously treated with a DAA-containing regimen. In POLARIS-1, patients with HCV genotype 1 infection who had previously received a regimen containing an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive either the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the protease inhibitor voxilaprevir (150 patients) or matching placebo (150 patients) once daily for 12 weeks. Patients who were infected with HCV of other genotypes (114 patients) were enrolled in the sofosbuvir-velpatasvir-voxilaprevir group. In POLARIS-4, patients with HCV genotype 1, 2, or 3 infection who had previously received a DAA regimen but not an NS5A inhibitor were randomly ass...
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the first 12weeks 11.9% and 5.9% of the patients required dose modifications of ribavirin and peginterferon alfa-2a, respectively and 2 (3.0%) and 17 (25.4%) patients had haemoglobin ,8.5 g/dL and ≥8.5 but ,10 g/dL respectively. Adverse... more
the first 12weeks 11.9% and 5.9% of the patients required dose modifications of ribavirin and peginterferon alfa-2a, respectively and 2 (3.0%) and 17 (25.4%) patients had haemoglobin ,8.5 g/dL and ≥8.5 but ,10 g/dL respectively. Adverse events reported in at least 15% of patients included fatigue (52.9%), nausea (26.5%), headache (25.0%), skin disorder (23.5%), dysgeusia (19.1%), pruritus (19.1%), myalgia (17.6%), anaemia (16.2%) andarthralgia (16.2%). Conclusion: Real world experience with BOC plus peginterferon alfa2a/ribavirin in Germany show similar virological outcomes and side effects to the phase 3 trials. Week 8 HCV RNA values essential to determine suitability for reduced treatment duration were not collected in a significant proportion of patients.
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The long-term therapeutic efficacy of alpha IFN and the influence of preC variants on the type of response were evaluated in 25 patients with chronic hepatitis B, 14 HBeAg and 11 antiHBe positive patients, treated with alpha IFN and... more
The long-term therapeutic efficacy of alpha IFN and the influence of preC variants on the type of response were evaluated in 25 patients with chronic hepatitis B, 14 HBeAg and 11 antiHBe positive patients, treated with alpha IFN and monitored for at least four years after discontinuing therapy. In both groups of patients, serum HBV-DNA became frequently undetectable by DNA dot blot during treatment, suggesting that alpha IFN has an antiviral effect both on HBeAg and antiHBe positive chronic carriers. However, long term follow up showed that the loss of viral DNA in antiHBe carriers was only transient, because all responder patients relapsed from 1 to 48 months after IFN withdrawal. In the HBeAg positive carriers, selection for preC mutants was observed at the end of follow up in 2 patients who seroconverted to antiHBe and remained viremic. Both the frequent occurrence of reactivations in antiHBe compared to HBeAg carriers, and the association of IFN therapy with preC mutant virus selection during long term post-treatment follow up observed in this study, indicate that preC variants are more resistant to IFN therapy than preC wild type HBV. Our data suggest therefore, that IFN therapy may be less frequently able to induce a permanent remission in patients infected with preC mutants.
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Research Interests: Medicine, Hepatitis C, Hepatology, Liver diseases, Serology, and 15 moreHumans, Internal Medicine, Female, Male, Hepatitis C Virus, Hepatitis, Liver Transplantation, Recurrence, Clinical Sciences, Adult, Blood Transfusion, Orthotopic Liver Transplantation, Seroconversion, Medical and Health Sciences, and Medical biochemistry and metabolomics
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Research Interests: Biology, Medicine, Biological Sciences, Hepatitis B, Humans, and 15 moreMutation, Chronic Disease, Female, Male, Polymerase Chain Reaction, Middle Aged, Adult, Amino Acid Sequence, Base Sequence, Hepatitis B virus, Chronic Liver Disease, Molecular Sequence Data, frameshift mutation, stop codon, and Medical and Health Sciences
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The transcription factor T-bet regulates the production of interferon-γ and cytotoxic molecules in effector CD8 T cells, and its expression correlates with improved control of chronic viral infections. However, the role of T-bet in... more
The transcription factor T-bet regulates the production of interferon-γ and cytotoxic molecules in effector CD8 T cells, and its expression correlates with improved control of chronic viral infections. However, the role of T-bet in infections with differential outcome remains poorly defined. Here, we report that high expression of T-bet in virus-specific CD8 T cells during acute hepatitis B virus (HBV) and hepatitis C virus (HCV) infection was associated with spontaneous resolution, whereas T-bet deficiency was more characteristic of chronic evolving infection. T-bet strongly correlated with interferon-γ production and proliferation of virus-specific CD8 T cells, and its induction by antigen and IL-2 stimulation partially restored functionality in previously dysfunctional T-bet-deficient CD8 T cells. However, restoration of a strong interferon-γ response required additional stimulation with IL-12, which selectively induced the phosphorylation of STAT4 in T-bet(+) CD8 T cells. The ob...
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CTL escape mutations have been described during acute hepatitis C in patients who developed chronic disease later on. Our aim was to investigate the mutual relationship between HCV specific CD8+ T cells and evolution of the viral sequence... more
CTL escape mutations have been described during acute hepatitis C in patients who developed chronic disease later on. Our aim was to investigate the mutual relationship between HCV specific CD8+ T cells and evolution of the viral sequence during early acute HCV infection. We sequenced multiple clones of NS3 1406 epitope in 4 HLA-A*02 patients with acute hepatitis C genotype 1b infection. Pentamers specific for the variants were used to monitor the corresponding CD8+ T cell response. We observed outgrowth of mutations, which induced only a weak and thus potentially insufficient CD8+ T cell response. In one patient we observed outgrowth of variant epitopes with similarities to a different genotype rather than de novo mutations most probably due to a lack of responsiveness to these likely pre-existing variants. We could show that in acute hepatitis C CTL escape mutations occur much earlier than demonstrated in previous studies. The adaption of the virus to a new host is characterized b...
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Two overlapping T-cell sites of the nucleocapsid antigen (HBc) of Hepatitis B Virus (HBV) (amino acids (aa) 120-140) and a B-cell epitope of the pre-S(2) region of the HBV surface antigen (aa 133-140) were expressed as a fusion protein... more
Two overlapping T-cell sites of the nucleocapsid antigen (HBc) of Hepatitis B Virus (HBV) (amino acids (aa) 120-140) and a B-cell epitope of the pre-S(2) region of the HBV surface antigen (aa 133-140) were expressed as a fusion protein with the subunit B of Escherichia coli heat labile enterotoxin (LT-B) in attenuated salmonellae (aroA Salmonella dublin SL1438). When Balb/c (haplotype H-2d) mice were fed salmonellae expressing LT-B or the LT-B/HBV fusion protein they developed serum IgG anti-LT-B antibodies and splenic cells reactive to LT-B. C57BL/10 (H-2b), in contrast, showed anti-LT-B antibody titres, but no splenic cell priming to LT-B. Neither in Balb/c nor in C57BL/10 mice could an antibody response to the fused HBV antibody binding site be demonstrated. In C57BL/10, however, an HBc T-cell epitope fused to LT-B primed a splenic cell response to an analogous synthetic peptide (HBc aa 121-145) in four out of five mice after three oral immunizations. This is the first descriptio...
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In hepatitis B virus infection, viral elimination is dependent on an efficient antiviral T cell response which is not detectable in chronic hepatitis B. Therefore, new therapeutic concepts focus on T cell activation, such as epitope-based... more
In hepatitis B virus infection, viral elimination is dependent on an efficient antiviral T cell response which is not detectable in chronic hepatitis B. Therefore, new therapeutic concepts focus on T cell activation, such as epitope-based T cell-targeted vaccines. However, with the development of peptide-based vaccines in mind, viral mutations frequently described in hepatitis B within known immunodominant helper epitopes may have an influence on peptide selection. Mutant peptides within immunodominant epitopes (aa 1-20, aa 91-105, and aa 143-157) at position 12, 14, 93, 97, 147, 151, 153, and 155 were tested with peripheral blood mononuclear and specific clone cells for their ability to induce proliferation, produce cytokines, induce T cell receptor down-regulation or antagonize wild-type activity of the hepatitis B core antigen-specific CD4+ T cell clones. Five variants could not induce T cell proliferation or cytokine production when the variants were presented alone. Coincubation with wild-type epitopes leads to T cell activation showing that the variants do not act as T cell receptor antagonists for hepatitis B virus-specific CD4+ T cells. In contrast, five other variants and wild-type peptides stimulated CD4+ T cell proliferation and production of Th1 cytokines. Our data demonstrate that frequently occurring mutations within immunodominant epitopes have rather a nonstimulatory than a strengthening effect and thus should not included in a vaccine.
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Research Interests: Pharmacology, Technology, Biological Sciences, Humans, Electroporation, and 16 moreFemale, Male, DNA vaccines, T lymphocytes, Middle Aged, Adult, Interleukins, Recombinant Proteins, Standard of Care, Molecular Targeted Therapy, Polyethylene Glycols, Ribavirin, Antiviral Agents, Interferon Alpha, Viral Load, and Combined Modality Therapy
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In acute hepatitis C virus (HCV) infection only 20-50% of patients spontaneously clear the virus. To characterise the immune reaction during that phase we studied the response of peripheral blood mononuclear cells (PBMC) to the... more
In acute hepatitis C virus (HCV) infection only 20-50% of patients spontaneously clear the virus. To characterise the immune reaction during that phase we studied the response of peripheral blood mononuclear cells (PBMC) to the recombinant HCV proteins core, non-structural protein 3 (NS3), NS4, and NS5 in 14 patients with acute hepatitis C. All eight patients with self-limited disease compared with two of six with evolving chronic infection showed an NS3- specific PBMC response (p = 0.015). Of 65 patients with established chronic hepatitis C, five showed a PBMC response to NS3. NS3-specific CD4 T-cell clones from patients with self-limited infection predominantly produced interferon-gamma and may thus support cytotoxic effector mechanisms important for viral clearance.
Research Interests: Hepatitis C, Humans, Hepatitis C Virus, Lancet, T lymphocytes, and 5 moreAged, Middle Aged, Genotype, Adult, and Acute Disease
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Research Interests: Histology, Infectious Diseases, Hepatitis C, Biopsy, Biological Sciences, and 19 moreCell line, Humans, Liver, Virus, Female, Male, Hepatitis C Virus, Liver Transplantation, Infectious, Recurrence, Middle Aged, Genotype, Time Factors, Liver Failure, Graft Rejection, Enzyme Linked Immunosorbent Assay, Antigen, Liver function tests, and Interferon gamma
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Background/Aims: Pulmonary side effects of interferon-α therapy of chronic hepatitis C seem to be rare. So far, only two cases of sarcoidosis in association with interferon-α treatment of chronic hepatitis C have been... more
Background/Aims: Pulmonary side effects of interferon-α therapy of chronic hepatitis C seem to be rare. So far, only two cases of sarcoidosis in association with interferon-α treatment of chronic hepatitis C have been described.Methods/Cases: We report on three patients who were treated with recombinant interferon-α2a for chronic hepatitis C, two of them in combination with ribavirin. These patients developed pulmonary
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Research Interests: DNA replication, Hepatology, Hepatitis B, Humans, Sequence alignment, and 13 moreMutation, Polymerase Chain Reaction, Clinical Sciences, Longitudinal Studies, Genotype, Genetic variation, Amino Acid Sequence, Virus infection, Hepatitis B virus, Amino Acid Substitution Rates, chronic hepatitis B, Antiviral Agents, and Molecular Sequence Data
Specific T cell responses during acute hepatitis B and during chronic hepatitis C have been described in detail. However, the T cell responses during the rare setting of acute hepatitis B virus (HBV) infection in the course of chronic... more
Specific T cell responses during acute hepatitis B and during chronic hepatitis C have been described in detail. However, the T cell responses during the rare setting of acute hepatitis B virus (HBV) infection in the course of chronic hepatitis C that eventually lead to clearance of both viruses are completely unknown. We analyzed the virus specific CD4+ and CD8+ T cell response during an acute HBV superinfection in a patient with chronic hepatitis C. The patient eliminated hepatitis C virus (HCV)-RNA and HBV-DNA from serum soon after the clinical onset of acute hepatitis B. The HBV specific T cell response found in this patient corresponds to the typical response that has been described in acute hepatitis B without chronic HCV infection. In contrast the hepatitis C specific immune response was similar to that generally found in chronic hepatitis C despite the fact that the patient also eliminated HCV-RNA. We hypothesize that the acute HBV infection induced a HBV specific T cell response which was associated with elimination HBV DNA and HCV-RNA, the latter possibly by bystander mechanisms, e.g. via secretion of cytokines. If such a non-specific bystander mechanism which has proven to be effective in the experimental setting and which is formally described here for a single patient can be shown to be a more general phenomenon, it may support the approach with new antiviral strategies, e.g. the induction of non-specific defense mechanisms against HCV.
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Research Interests: Treatment Outcome, Hepatitis C, Hepatology, Humans, Female, and 15 moreMale, Hepatocellular Carcinoma, Hepatitis C Virus, Liver Transplantation, Recurrence, Single Cell, Clinical Sciences, Middle Aged, Time Factors, Amino Acid Profile, Transient Response, Antiviral Agents, Orthotopic Liver Transplantation, Phosphate Buffer Saline, and Postoperative Complications
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Research Interests: Cell Biology, Biological Sciences, Spleen, Cell line, Cell Differentiation, and 16 moreHumans, Mice, Methylation, Animals, Calcium Signaling, Phosphorylation, Experimental Medicine, Arginine, Transfection, B Lymphocytes, Amino Acid Sequence, Protein Binding, Bone Marrow Cells, Interleukin, B cell antigen receptor (BCR), and Molecular Sequence Data
... Norbert H. Gruener , MD; Malte Heeg , MD; Martin Obermeier , MD; Axel Ulsenheimer , MD; Bijan Raziorrouh , MD; Helmut Diepolder , MD; Reinhart Zachoval , MD ... 2 , 3 To our knowledge, at this time, there is no effective method to... more
... Norbert H. Gruener , MD; Malte Heeg , MD; Martin Obermeier , MD; Axel Ulsenheimer , MD; Bijan Raziorrouh , MD; Helmut Diepolder , MD; Reinhart Zachoval , MD ... 2 , 3 To our knowledge, at this time, there is no effective method to prevent HCV infection in a person who has a ...
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In acute and chronic viral disease the specific response of CD4+ T lymphocytes to certain viral proteins is an essential part of antiviral effector mechanisms. In hepatitis C virus infection, the contribution of the immune system and... more
In acute and chronic viral disease the specific response of CD4+ T lymphocytes to certain viral proteins is an essential part of antiviral effector mechanisms. In hepatitis C virus infection, the contribution of the immune system and particularly of CD4+ T lymphocytes to the pathogenesis of disease is unknown. We serially determined the peripheral blood CD4+ T lymphocyte response to several recombinant hepatitis C virus proteins (core, NS3, NS4, NS5) and 17 overlapping synthetic peptides derived from the core sequence over up to 48 months in 43 patients with chronic hepatitis C; of these, 16 had been treated with interferon alfa (IFN). Twelve of 27 untreated patients, 4 of 4 sustained responders to IFN, 7 of 8 patients with a transient response, and 1 of 4 nonresponders showed a proliferative response to hepatitis C virus proteins. The hepatitis C virus core protein was the most immunogenic protein, and fine analysis with peptides indicated amino acids 23 to 42, 66 to 85, and 131 to 150 as immunodominant regions. In a subgroup of nine patients, proliferation assays were performed before or during IFN. In this subgroup, sustained responders but not those with a transient or no response to IFN showed a specific CD4+ immune reaction to hepatitis C viral antigens (P < .05). Infection with hepatitis C virus genotype 3a was significantly associated with a sustained response to IFN (P < .05). In general, a CD4+ T lymphocyte response was more common in patients with chronic hepatitis C who responded to interferon-alpha as compared with nonresponders.(ABSTRACT TRUNCATED AT 250 WORDS)
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Research Interests: Production, Histology, Comparative Study, Low Frequency, T cell receptor, and 18 moreHepatology, Humans, Liver Cirrhosis, Liver, Virus, Female, Male, Hepatitis C Virus, Single Cell, Clinical Sciences, Middle Aged, Adult, Biological markers, Epitopes, chronic hepatitis C, Blood cells, Interferon gamma, and Viral Load
The hepatitis B virus genome encodes a transcriptional transactivator protein designated HBxAg. We have investigated whether this antigen is a target structure for human T-lymphocytes. Using recombinant HBxAg protein, we found... more
The hepatitis B virus genome encodes a transcriptional transactivator protein designated HBxAg. We have investigated whether this antigen is a target structure for human T-lymphocytes. Using recombinant HBxAg protein, we found HBxAg-specific stimulation of peripheral blood mononuclear cells in patients with acute hepatitis B virus infection (6 of 6) and chronic hepatitis B virus infection (6 of 17) but not in healthy individuals. With HBxAg-specific synthetic polypeptides, several T-cell epitopes were identified. Most were located in the carboxyterminal half of the HBxAg protein. Five T-cell clones specific for a T-cell epitope located at the carboxyterminal region of HBxAg were established and found to belong to the CD2/CD4-positive, CD8-negative subtype. These data establish for the first time HBxAg as an antigen in the cellular immune response.
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Research Interests: Immune response, Flow Cytometry, Hepatitis C, Hepatology, Humans, and 20 moreVirus, Female, Male, Hepatitis C Virus, Functional impairment, Clinical Sciences, Middle Aged, Adult, Specific Activity, Deficiency, T cell activation, Cell Proliferation, Sensitivity and Specificity, Deficit, chronic hepatitis C, Secretion, Down-Regulation, Interferon gamma, Transforming Growth Factor, and Acute Disease
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Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance1 1The Bundesministerium für Bildung und Forschung and the European Union, as sponsors of the study, had no role in study design, data collection, analysis, or interpretation or in the writing and the decision t...more
Acute hepatitis C virus infection accounts for approximately 20% of cases of acute hepatitis today. The aim of this study was to define the natural course of the disease and to contribute to the development of treatment strategies for... more
Acute hepatitis C virus infection accounts for approximately 20% of cases of acute hepatitis today. The aim of this study was to define the natural course of the disease and to contribute to the development of treatment strategies for acute hepatitis C virus. The diagnosis of acute hepatitis C virus in 60 patients was based on seroconversion to anti-hepatitis C virus antibodies or clinical and biochemical criteria and on the presence of hepatitis C virus RNA in the first serum sample. Fifty-one of 60 (85%) patients presented with symptomatic acute hepatitis C virus. In the natural (untreated) course of acute symptomatic hepatitis C (n = 46), spontaneous clearance was observed in 24 patients (52%), usually within 12 weeks after the onset of symptoms, whereas all asymptomatic patients (n = 9) developed chronic hepatitis C. The start of antiviral therapy (interferon-alpha with or without ribavirin) beyond 3 months after the onset of acute hepatitis induced sustained viral clearance in 80% of treated patients. The management of acute hepatitis C has to take into account the high rate of spontaneous viral clearance within 12 weeks after the onset of symptomatic disease. Treatment of only those patients who remain hepatitis C virus RNA positive for more than 3 months after the onset of disease led to an overall viral clearance (self-limited and treatment induced) in 91% of patients, and unnecessary treatment was avoided in those with spontaneous viral clearance. Patients with asymptomatic acute hepatitis C virus infection are unlikely to clear the infection spontaneously and should be treated as early as possible.
Research Interests: Gastroenterology, European Union, Treatment Outcome, Adolescent, Hepatitis C, and 18 moreHumans, Female, Male, Follow-up studies, Hepatitis C Virus, Data Collection, Clinical Sciences, Middle Aged, Adult, Study design, Combination drug therapy, Recombinant Proteins, Neurosciences, Polyethylene Glycols, Ribavirin, Antiviral Agents, Interferon Alpha, and Acute Disease
Down-regulation of hepatitis C virus (HCV)-specific CD4(+) T-cell responses is a hallmark of chronic viral persistence in acute hepatitis C. FOXP3(+)CD25(+)CD4(+) regulatory T cells can modulate HCV-specific immune responses in vitro, but... more
Down-regulation of hepatitis C virus (HCV)-specific CD4(+) T-cell responses is a hallmark of chronic viral persistence in acute hepatitis C. FOXP3(+)CD25(+)CD4(+) regulatory T cells can modulate HCV-specific immune responses in vitro, but the role of virus-specific regulatory T cells in the pathogenesis of chronic viral persistence is unknown. Two novel HLA-DR15 tetramers were synthesized to study the kinetics and phenotype of FOXP3(+)-expressing HCV-specific CD4(+) T cells from 10 patients with acute hepatitis C and 15 patients with chronic hepatitis C. In acute hepatitis C, generally only a low percentage of HCV-specific CD4(+) T cells expressed FOXP3(+) (mean of 2.5% in patients with self-limited acute hepatitis C vs 2.4% in patients with evolving chronic hepatitis C). Although distinct but short-lived increases in virus-specific FOXP3(+)CD4(+) T cells occurred in 3 patients (30%, 26%, and 7% of tet(+) CD4(+) T cells, respectively), these did not correlate with the evolution of chronic hepatitis C. HCV-specific FOXP3(+)CD4(+) T cells displayed a distinct phenotype, with only 10% expressing CD25 and 40% being CD127low. Interestingly, this phenotype of FOXP3(+)CD4(+) T cells was already expanded in bulk CD4(+) T cells in patients with chronic hepatitis C. Although short-lived increases in HCV-specific FOXP3(+)CD4(+) T cells occur during the course of acute hepatitis C, we could not demonstrate an association of HCV-specific regulatory T cells and persistent viremia.
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Recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) is a major cause of transplant failure in HCV-positive patients. We retrospectively assessed the efficacy and safety of antiviral therapy and determined the... more
Recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) is a major cause of transplant failure in HCV-positive patients. We retrospectively assessed the efficacy and safety of antiviral therapy and determined the factors influencing sustained virologic response (SVR) in LT recipients. Between 1998 and 2007, we treated 36 LT recipients for hepatitis C cirrhosis and subsequent HCV recurrence (27 genotype 1 and 9 genotypes 2/3) with pegylated interferon alpha-2a (180 microg/week), pegylated interferon alpha-2b (1.5 microg/kg per week), or standard interferon alpha-2b (3 MIU 3X/week) plus ribavirin (600-1200 mg/day) for 48 weeks. SVR was achieved in seven of 27 (26%) of genotype 1 patients versus nine of nine (100%) genotype 2/3 patients (P=0.0001). Early virologic response at week 12 was associated with permanent viral clearance. Side effects included cytopenia and acute hearing loss, but rate of therapy withdrawal and dose reduction was low. Combination therapy in patients with HCV reinfection after LT yields an excellent SVR rate in genotype 2/3 patients, but remains unsatisfactory in genotype 1 patients. Virologic response at week 12 (early virologic response) can determine whether therapy should be continued or not.
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Cells respond to tumour necrosis factor-α (TNF-α) via binding to 75-kDa (type A) and 55-kDa (type B) receptors which have different intracellular signalling pathways and can also circulate as soluble molecules. Both receptors are... more
Cells respond to tumour necrosis factor-α (TNF-α) via binding to 75-kDa (type A) and 55-kDa (type B) receptors which have different intracellular signalling pathways and can also circulate as soluble molecules. Both receptors are co-expressed in many tissues, but their relative contributions to cellular TNF responses is for most situations unknown.In patients with viral and non-viral inflammatory liver diseases serum