Immunology of Viral Hepatitis and Infections in Liver Cirrhosis
Focus
The Impact of immune responses on chronic hepatitis B virus
Worldwide more than 250 million people are chronically infected with hepatitis B virus (HBV) with 650.000 HBV related death annually. Current treatment options for chronic hepatitis B in industrialized countries are the cytokine interferon alfa or direct antivirals, so called nucleos(t)id-analoga (NA). NA can suppress viral replication very efficiently. However, only a small percentage of patients will achieve a status of functional cure, which is measured by the loss of the HBV envelope antigen (HBsAg). The reason is that NA therapy only inhibits the generation of new virions, but does not directly affect the mini-chromosome of HBV that is located in the nucleus of the liver cell. This so called covalently closed circular HBV DNA (cccDNA), the template of HBV, might be eliminated by new strategies involving immune responses. One focus of our research group is to understand mechanisms of the immune system to clear HBV and to identify new targets for therapeutic interventions for HBV cure.
The impact of HCV cure on the immune system
Worldwide 50-70 million people are chronically infected with HCV. Chronic hepatitis C leads to liver cirrhosis and increases the risk to develop liver cancer. In addition, infection with HCV can cause extrahepatic manifestations such as chronic fatigue or certain rheumatic diseases. Chronic HCV infection leads also to an altered and dysregulated immune response, which might also impact extrahepatic symptoms. Treatment with direct acting antivirals (DAA) have been established in 2014 and HCV cure can be achieved in more than 95% of treated patients. HCV cure prevents the development of cirrhosis and reduces the risk to develop liver cancer. However, the risk for cancer is not zero and extrahepatic manifestations are not always reversed. The short and long-term effect of HCV cure on the imbalanced immune system is a main focus of our research. A better understanding of immune responses in HCV might also foster the progress to find a vaccine against HCV which is important to achieve WHO elimination goals of HCV infection.
The impact of immune responses in chronic hepatitis E
Infection with the hepatitis E virus (HEV) is considered as the most common cause of acute viral hepatitis in developing as well as in developed countries. Infections in industrialized countries are mainly zoonotic infections with genotype 3, which is transmitted by consumption of raw or undercooked meat or viscera of infected animals, or through contaminated blood products.
Patients with acute hepatitis E usually recover spontaneously and clear the virus but immunosuppressed patients, such as solid organ transplant recipients, may develop chronic hepatitis E in about 50% of cases. Patients with chronic hepatitis E may develop cirrhosis within a few years. There is no approved drug for chronic hepatitis E. Interferon-α or ribavirin are off-label treatment options and if used associated with side effects. One focus of the research group is to understand how the immune system can be modified to clear chronic HEV infection. This could lead to new concepts to treat immunocompromised patients with chronic hepatitis E.
Understanding of the Cirrhosis Associated Immune Deficiency Syndrome
Liver cirrhosis is the end-stage of many chronic liver diseases such as chronic hepatitis virus infections. Complications of cirrhosis are ascites or hepatic encephalopathy, as well as esophageal varices bleeding, which defines decompensated cirrhosis. Patients with decompensated cirrhosis have a one-year cumulative mortality of roughly 50%. The main cause for this high mortality is infection, such as spontaneous bacterial peritonitis (SBP). One reason for the vulnerability for infections is thought to be the impaired immune defense of patients with advanced liver cirrhosis, known as liver cirrhosis associated immune deficiency syndrome. One focus of our research group is to investigate soluble and cellular immune responses in the blood and the ascites of patients with decompensated liver cirrhosis to understand mechanisms of the immune deficiency and ways to manipulate and improve this condition.
Mouse models: To decode the effect of immune modulatory therapies on heterologous viral infections
Chronic viral infections are still a global health burden. For many of these infections therapy options for viral clearance are limited. One strategy to overcome chronicity is to target the host immune responses. Therefore, deeper insides in the mechanism how chronicity develops and how immune modulatory interventions (e.g. α-PD-L1 antibody therapy) might influence and shape the antiviral immune response is needed.
One focus of the research group is to use the well-established lymphocytic choriomeningitis virus (LCMV) mouse model to investigate new concepts of immune modulatory treatment options on viral clearance and modulation of the host immune responses.
Focus
The Impact of immune responses on chronic hepatitis B virus
Worldwide more than 250 million people are chronically infected with hepatitis B virus (HBV) with 650.000 HBV related death annually. Current treatment options for chronic hepatitis B in industrialized countries are the cytokine interferon alfa or direct antivirals, so called nucleos(t)id-analoga (NA). NA can suppress viral replication very efficiently. However, only a small percentage of patients will achieve a status of functional cure, which is measured by the loss of the HBV envelope antigen (HBsAg). The reason is that NA therapy only inhibits the generation of new virions, but does not directly affect the mini-chromosome of HBV that is located in the nucleus of the liver cell. This so called covalently closed circular HBV DNA (cccDNA), the template of HBV, might be eliminated by new strategies involving immune responses. One focus of our research group is to understand mechanisms of the immune system to clear HBV and to identify new targets for therapeutic interventions for HBV cure.
The impact of HCV cure on the immune system
Worldwide 50-70 million people are chronically infected with HCV. Chronic hepatitis C leads to liver cirrhosis and increases the risk to develop liver cancer. In addition, infection with HCV can cause extrahepatic manifestations such as chronic fatigue or certain rheumatic diseases. Chronic HCV infection leads also to an altered and dysregulated immune response, which might also impact extrahepatic symptoms. Treatment with direct acting antivirals (DAA) have been established in 2014 and HCV cure can be achieved in more than 95% of treated patients. HCV cure prevents the development of cirrhosis and reduces the risk to develop liver cancer. However, the risk for cancer is not zero and extrahepatic manifestations are not always reversed. The short and long-term effect of HCV cure on the imbalanced immune system is a main focus of our research. A better understanding of immune responses in HCV might also foster the progress to find a vaccine against HCV which is important to achieve WHO elimination goals of HCV infection.
The impact of immune responses in chronic hepatitis E
Infection with the hepatitis E virus (HEV) is considered as the most common cause of acute viral hepatitis in developing as well as in developed countries. Infections in industrialized countries are mainly zoonotic infections with genotype 3, which is transmitted by consumption of raw or undercooked meat or viscera of infected animals, or through contaminated blood products.
Patients with acute hepatitis E usually recover spontaneously and clear the virus but immunosuppressed patients, such as solid organ transplant recipients, may develop chronic hepatitis E in about 50% of cases. Patients with chronic hepatitis E may develop cirrhosis within a few years. There is no approved drug for chronic hepatitis E. Interferon-α or ribavirin are off-label treatment options and if used associated with side effects. One focus of the research group is to understand how the immune system can be modified to clear chronic HEV infection. This could lead to new concepts to treat immunocompromised patients with chronic hepatitis E.
Understanding of the Cirrhosis Associated Immune Deficiency Syndrome
Liver cirrhosis is the end-stage of many chronic liver diseases such as chronic hepatitis virus infections. Complications of cirrhosis are ascites or hepatic encephalopathy, as well as esophageal varices bleeding, which defines decompensated cirrhosis. Patients with decompensated cirrhosis have a one-year cumulative mortality of roughly 50%. The main cause for this high mortality is infection, such as spontaneous bacterial peritonitis (SBP). One reason for the vulnerability for infections is thought to be the impaired immune defense of patients with advanced liver cirrhosis, known as liver cirrhosis associated immune deficiency syndrome. One focus of our research group is to investigate soluble and cellular immune responses in the blood and the ascites of patients with decompensated liver cirrhosis to understand mechanisms of the immune deficiency and ways to manipulate and improve this condition.
Mouse models: To decode the effect of immune modulatory therapies on heterologous viral infections
Chronic viral infections are still a global health burden. For many of these infections therapy options for viral clearance are limited. One strategy to overcome chronicity is to target the host immune responses. Therefore, deeper insides in the mechanism how chronicity develops and how immune modulatory interventions (e.g. α-PD-L1 antibody therapy) might influence and shape the antiviral immune response is needed.
One focus of the research group is to use the well-established lymphocytic choriomeningitis virus (LCMV) mouse model to investigate new concepts of immune modulatory treatment options on viral clearance and modulation of the host immune responses.
Markus Cornberg is W3-Professor Infectious Diseases with a focus on Hepatology and Deputy Director of the Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology at Hannover Medical School, Germany. Since 2019, he is Clinical Director Helmholtz Centre for Infection Research and Director of the Centre for Individualized Infection Medicine (CIIM). Prof. Cornberg is Medical Executive Director of the German Liver Foundation. Since 2007, Prof. Cornberg has coordinated the German guideline on the management of hepatitis B virus infection. From 2017 to 2020, he served on the Scientific Committee and Governing Board of the European Association for the Study of the Liver (EASL). He has been Associate Editor of the Journal of Hepatology since 2019. His basic science research focus is the investigation of cellular immune responses for disease progression and treatment response in patients with viral hepatitis. Prof. Cornberg has published >300 original scientific papers as well as review articles.
Anke Kraft is a senior scientist in the Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology at Hannover Medical School and in the Center for Individualized Infection Medicine (CIIM). She studied biology in Göttingen and Braunschweig and received her PhD from the University of Würzburg. After research stays at the University of Essen, Worcester (MA, USA) and Hannover, she has been leading the research group "Immunology of viral hepatitis and infections in liver cirrhosis" together with Markus Cornberg since 2018. She is a member of the German Society for Virology (GfV) and for Immunology (DGFI) and works as Review Editor at Frontiers Immunology. Anke Kraft has been working on immune responses in chronic viral infections for more than 20 years. She is interested in developing novel strategies to restore T cell responses in chronic viral infections and patients with advanced liver cirrhosis. Her current work includes studying hepatitis virus-infected patients and working on knowledge graphs to better understand the patient immune system, as well as chronic mouse models.
Research projects
Hannover Hepatitis Biobank Cohort (HHBC)
For the analysis of immune responses in patients with viral hepatitis and liver cirrhosis, we have established the Hannover Hepatitis Biobank Cohort (HHBC). Currently, we process biomaterial from 40-50 patients per week, which includes among others whole blood, PBMC, plasma, serum, urine, stool, ascites and liver biopsies. Biomaterial processing takes place according to established SOPs in our laboratory. We work closely with the Hannover Unified Biobank (HUB), which includes the use of CentraXX (Kairos) for biomaterial management and long-term storage of samples at the HUB. In the near future, we plan to expand and establish new cooperation with groups in DZIF and at MHH and HZI.
Analysis of HBV-specific T cell function and response to immunomodulation in relation to HBsAg and HBcrAg in patients with chronic hepatitis B virus infection
Hepatitis B virus (HBV)-specific T cells are main effector cells in the control of HBV infection and HBsAg is suggested to be a critical factor in the impaired immune response, a hallmark of chronic HBV infection. In addition to HBsAg, other viral markers such as HBcrAg are available. We have recently analyzed the association of these markers with the HBV-specific T cell responses. However, the impact of immunomodulation on the T cells in relation to HBV marker is not well defined yet. This will be important if these markers might be used for patient stratification for novel immune based therapies aimed at functional HBV cure, which is a major topic of the TTU Hepatitis of the German Center for Infection Research (DZIF). We are currently investigating HBV-specific T cell responses and the response to checkpoint inhibition (anti-PD-L1) in combination with other immune modifiers such as epigenetic modulators (Figure 1) in vitro in patients with chronic HBV infection with different HBsAg and HBcrAg levels from our Hannover Hepatitis Biobank Cohort (HHBC). We are working with data scientists to develop a knowledge-driven approach to discover factors potentially associated with HBsAg loss in HBV infected patients (ImProVIT, funded by the Volkswagen Foundation and the Lower Saxony Ministry for Science and Culture (MWK)).
Impact of T cell responses in patients with chronic hepatitis B after stopping nucleos(t)ide analogue (NA) therapy
We have initiated prospective clinical trials investigating a structured treatment termination of direct acting antiviral nucleos(t)ide analogues (NA) in patients with chronic hepatitis B before they achieve functional cure (HBsAg loss). The results of the first trial were pivotal for the concept that stopping NA therapy and subsequent HBV DNA rebound may induce immune responses, which could promote later HBsAg loss, the equivalent of functional cure. Now, our research group investigates detailed aspects of innate and adaptive immune responses after structured cessation of NA treatment to elucidate the immune mechanisms leading to functional cure of HBV. In a project within the excellence cluster RESIST, we currently focus on the role of γδ T cells, which are unconventional T cells that are enriched in the liver.
Deciphering long-term immune imprints of HCV infection after viral elimination
The main long-term consequence of chronic hepatitis C is the development of liver cirrhosis, which is associated with a significant risk of hepatocellular carcinoma (HCC). Furthermore, HCV infection can lead to extrahepatic manifestations such as chronic fatigue, diabetes mellitus or vasculitis. Meanwhile, direct acting antivirals (DAA) are available that are well tolerated and result in sustained virological response (SVR) rates of more than 95% leading to significant reduction of liver morbidity and mortality. However, not all sequalae of chronic hepatitis C seem to be completely reversible after SVR. Patients with advanced fibrosis or cirrhosis have a residual risk for HCC. Impaired quality of life or extrahepatic manifestations such as cryoglobulinemic vasculitis are only partially improved or not reversible in all patients. Interestingly, recently published studies including our own have shown that HCV infection can leave an immunological imprint or scar after SVR, and the impaired immune response characteristic of chronic HCV infection is only partially restored. Together with data scientists we investigate the long-term consequences of HCV infection on the immune system in multiple cohorts (Hannover Hepatitis Biobank Cohort (HHBC)) using omics technology in the BMBF funded project “NetFLID”. The overall aim of NetFLID is to develop a data integration and analysis platform that leverages network medicine and AI methods to decipher infectious disease mechanisms at multiple levels, from the epigenome and transcriptome to the immunoproteome and metabolome, including over time
Characterization of unconventional T cell responses in chronic hepatitis E
Hepatitis E virus (HEV) causes a liver infection that often resolves on its own, but can become chronic in immunocompromised individuals. Most cases in Germany are zoonotic HEV genotype 3, transmitted through contaminated food. Treatment of chronic HEV genotype 3 infection is challenging. Immune responses, including CD4+ and CD8+ T cells, are critical for HEV elimination as shown previously, but the role of unconventional T cells (MAIT cells, γδ T cells) has been poorly studied. These T cells, which bridge innate and adaptive immunity, are found in the liver and may influence HEV pathogenesis. In two medical doctorate projects funded by the DZIF, we are currently investigating the impact of MAIT and γδ T cells in HEV infections.
Characterization of T cell responses in cirrhosis associated immune deficiency syndrome
Liver cirrhosis is the end stage of many chronic liver diseases such as chronic hepatitis virus infection. Patients with advanced cirrhosis often develop hepatic decompensation associated with systemic inflammation, which may eventually lead to acute chronic liver failure (ACLF). An important cause of systemic hyperinflammation is a dysregulated, exuberant immune response in the ascites in the abdominal cavity. We are currently investigating the role of unconventional (MAIT cells, ,γδ T cells) and conventional T cells (CD4+ and CD8+ T cells) in the ascites immune compartment. For this purpose, we are using biospecimens collected from patients in our prospective patient registry INFEKTA.
Publications
1. Aliabadi E, Urbanek-Quaing M, Maasoumy B, Bremer B, Grasshoff M, Li Y, Niehaus CE, Wedemeyer H, Kraft ARM, Cornberg M. Impact of HBsAg and HBcrAg levels on phenotype and function of HBV-specific T cells in patients with chronic hepatitis B virus infection. Gut. 2022 Nov;71(11):2300-2312. doi: 10.1136/gutjnl-2021-324646.
2. Cornberg M, Mischke J, Kraft AR, Wedemeyer H. Immunological scars after cure of hepatitis C virus infection: Long-HepC? Curr Opin Immunol. 2023 Jun;82:102324. doi: 10.1016/j.coi.2023.102324.
3. Oltmanns C, Liu Z, Mischke J, Tauwaldt J, Mekonnen YA, Urbanek-Quaing M, Debarry J, Maasoumy B, Wedemeyer H, Kraft ARM, Xu CJ, Cornberg M. Reverse inflammaging: Long-term effects of HCV cure on biological age. J Hepatol. 2023 Jan;78(1):90-98. doi: 10.1016/j.jhep.2022.08.042.
4. Niehaus CE, Strunz B, Cornillet M, Falk CS, Schnieders A, Maasoumy B, Hardtke S, Manns MP, Kraft ARM, Björkström NK, Cornberg M. MAIT Cells Are Enriched and Highly Functional in Ascites of Patients With Decompensated Liver Cirrhosis. Hepatology. 2020 Oct;72(4):1378-1393. doi: 10.1002/hep.31153.
5. Klein S, Mischke J, Beruldsen F, Prinz I, Antunes DA, Cornberg M, Kraft ARM. Individual Epitope-Specific CD8+ T Cell Immune Responses Are Shaped Differently during Chronic Viral Infection. Pathogens. 2023 May 14;12(5):716. doi: 10.3390/pathogens12050716.
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