Immune Response and Immunolmodulation in Chronic Hepatiitis B Virus Infection

Abstract

Despite the presence of an effective vaccine since 1982, chronic hepatitis B virus infection (CHB) still ranks among the highest causes of mortality from infectious diseases worldwide. The studies presented in this thesis were performed to get a better insight into the anti-viral immune response after hepatitis B virus (HBV) infection, and to identify factors in this immune response that contribute to persistent disease. Dendritic cells (DC) play an important role in the induction of anti- viral immune responses. In this thesis we show that two important blood precursor DC, myeloid DC and plasmacytoid DC, are functionally impaired in patients with chronic hepatitis B and this might be an important mechanism by which HBV evades an adequate immune response, leading to viral persistence and disease chronicity. Information about character and grade of the intrahepatic immune response in viral hepatitis is important for evaluation of disease stage and effect of therapy. Complications like haemorrhage provide a limitation to frequently performing standard tissue needle biopsies. The Fine-needle-aspiration-biopsy (FNAB) is an easy and atraumatic alternative and we show that flow cytometry of fine-needle-aspiration- biopsy of the liver allows reliable analysis of lymphocytes obtained from the intrahepatic compartment, in patients with viral hepatitis. Subsequently, the FNAB is used to show that there likely is an important role for intrahepatic HBV-specific CD8+ T-cells in clearing acute HBV infection. Furthermore, we have attempted to boost the impaired T-cell responses in patients with chronic HBV infection, using conventional anti-viral therapy. In in vivo immunization (IVI) of CHB patients, following rapid virus suppression by interferon-lamivudine combination therapy, lamivudine was withdrawn intermittently during continued interferon (IFNα) therapy. Although initially IVI was able to transiently suppress viral replication in two patients with CHB, in a subsequent pilot study the magnitude of the induced T-cell response was insufficient to cause a sustained virological effect in the majority of patients. It is unknown why treatment with IFNα leads to a response in only a minority of patients with chronic HBV. We show that in non-responders and not in responders there was a significant increase in the frequency of regulatory T cells (Treg) and IL-10 secreting cells during treatment with IFNα. Treg depletion resulted in increased proliferation capacity and increased frequencies of HBV-specific INFgamma-producing cells, but did not affect the frequency of IL-10 producing cells measured during the course of the treatment. This study indicates that there may be an important role for Treg in HBV- persistence during and after IFNα therapy