Immunopathogenesis Of Hepatitis Research Articles

Effects of immunosuppression and organ transplantation on the natural history and immunopathogenesis of hepatitis C virus infection

The hepatitis C virus (HCV) is recognized as the leading cause for parenterally transmitted hepatitis. It is characterized by a high propensity to chronicity. Several efforts have been directed towards understanding the natural history of chronic HCV infection and the immunopathogenic pathways involved in mediating liver injury in the non-immunosuppressed and immunosuppressed states. In the non-immunosuppressed setting, liver damage seems to be largely immune mediated. In contrast, in the non-immunosuppressed state, there are several other factors that may modify the natural course of the infection and play a role in mediating liver injury. In this review we will address the natural history, virological and immunological aspects of HCV infection. Also, the role played by immunosuppression and organ transplantation in modifying the course of the infection and the pathogenesis of liver injury will be discussed.

Immunopathogenesis of hepatitis C virus infection

ESOLUTION of acute hepatitis C is generally associR ated with detection of neutralizing antibodies, a high frequency of circulating HCV-specific T cells with a predominant production of Thl cytokines. In contrast, T cell responses in the peripheral blood are usually undetectable in the acute phase of disease and are oriented towards a predominant production of Th2 cytokines when infection becomes chronic. Therefore, different strengths and quality of T cell responses at the early stages of infection may influence the evolution of hepatitis C but the primary causes of these different behaviors are still undefined. A good proportion of patients with long-lasting chronic HCV infection display detectable levels of peripheral blood cytotoxic T lymphocyte (CTL) responses and produce neutralizing anti-envelope antibodies. Moreover, the frequency of intrahepatic HCVspecific CTL seems to be high in these patients, the CTL response is multispecific and the liver environment is characterized by a predominant production of Thl cytokines. Therefore, at this stage of infection the virus appears to have acquired the capacity to escape immune surveillance and to persist in the face of an active antiviral immune response. If these observations derived from in vitro studies actually reflect the strength and the quality of the immune responses in vivo, inhibition of viral replication rather than modulation of the immune response should represent the main objective of anti-HCV therapies once a chronic

Human gamma interferon production by cytotoxic T lymphocytes sensitized during hepatitis A virus infection

The production of interferon (IFN) during a chromium-51 release assay with hepatitis A virus (HAV)-infected fibroblasts and autologous peripheral blood lymphocytes from patients with acute HAV infection was studied to determine whether IFN plays a role in immunopathogenesis of hepatitis A infection in humans. Skin fibroblasts of eight patients after acute HAV infection and from two control persons without history of current or past HAV infection were infected with HAV. Peripheral blood lymphocytes were collected at different times after the onset of icterus and tested in a chromium-51 release assay against autologous HAV-infected skin fibroblasts for their cytolytic and IFN-producing activity. The IFN produced during the assay was characterized and found to have the properties of human gamma IFN. Cytotoxicity and gamma IFN release were virus specific. The cell types responsible for both functions were characterized and found to be in the HLA-dependent T8+ lymphocyte subset. Considering that gamma IFN has an antiviral effect on persistent HAV infection in vitro and that it probably accounts for stimulation of HLA class I antigen expression on hepatocytes, our experimental results presented here demonstrate that human gamma IFN produced by HAV-specific T cells may participate in pathogenesis of hepatitis A infection in humans.

Hepatitis B surface antigen specific cytotoxic T lymphocyte activity in hepatitis B virus infection.

Cytotoxic T lymphocyte (CTL) activity against HBs antigen (HBsAg)-coated autologous mononuclear cells as target cells was examined in hepatitis B virus infection. Target cells were prepared by coincubation of mononuclear cells with purified HBsAg in 0.5 mM CrCl3. The distribution and uniformity amounts of HBsAg on target cells was shown by immune fluorescence and by analyzing the fluorescence intensity with a fluorescent activated cell sorter. CTL activity was detected in 7 of 9 patients with acute hepatitis type B, in 4 of 11 chronic active hepatitis type B, in none of 8 healthy HBsAg carriers, and in none of 22 healthy volunteers. The antigen specificity of the cytotoxicity was confirmed by a blocking experiment with purified HBsAg and by cold target inhibition with HBsAg or bovine serum albumin (irrelevant antigen) coupled cold target cells. CTL lysed HBsAg coupled allogeneic target cells that shared HLA-A or B locus antigens. This finding suggests that HLA restriction may be involved in the killing mechanism. This HBsAg specific CTL clone may participate in the immunopathogenesis of hepatitis B virus infection.