The pathogenetic mechanisms responsible for the induction of hepatocellular injury and viral clearance in hepatitis B virus (HBV) infection remain to be determined. Considerable indirect evidence suggests that HBV specific cellular immune response plays a central role in these processes. Proof of this hypothesis is lacking because the appropriate model systems to test it have not existed. Furthermore, if the hypothesis is correct, the pathogenetically relevant HBV encoded target antigens are entirely unknown. The reagents, systems and expertise necessary to assess the role of the immune response in injury and clearance now exist in our laboratory. Therefore, the long term objective of this proposal is to characterize the human cellular immune response to the known HBV-encoded antigens in an effort to delineate the factors potentially involved in viral clearance and liver disease. The study will focus on the characteristics of HBV antigen specific T cell lines and clones derived from the site of infection and injury (liver) and also from the peripheral blood of patients with acute or chronic hepatitis-B. HBV antigen-specific T cells will be assessed for phenotype, fine specificity, HLA restriction and function by testing antigen specific helper, suppressor and cytotoxic activities and lymphokine production. Our preliminary results indicate that HBV nucleocapsid specific T cells present in the peripheral blood do not accurately reflect events occurring within the liver at the site of injury and viral synthesis. We, therefore, intend to expand these studies to the remaining HBV encoded antigens in this proposal. When such data is available it will be possible to determine if HBV antigen specific T cell activation, phenotype and function are pathogenetically related to virus induced injury and to viral clearance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI026626-02
Application #
3140455
Study Section
Pathology B Study Section (PTHB)
Project Start
1988-09-30
Project End
1991-08-31
Budget Start
1989-09-01
Budget End
1990-08-31
Support Year
2
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
San Diego
State
CA
Country
United States
Zip Code
92037
Boni, C; Bertoletti, A; Penna, A et al. (1998) Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B. J Clin Invest 102:968-75
Missale, G; Cariani, E; Lamonaca, V et al. (1997) Effects of interferon treatment on the antiviral T-cell response in hepatitis C virus genotype 1b- and genotype 2c-infected patients. Hepatology 26:792-7
Bertoni, R; Sidney, J; Fowler, P et al. (1997) Human histocompatibility leukocyte antigen-binding supermotifs predict broadly cross-reactive cytotoxic T lymphocyte responses in patients with acute hepatitis. J Clin Invest 100:503-13
Penna, A; Del Prete, G; Cavalli, A et al. (1997) Predominant T-helper 1 cytokine profile of hepatitis B virus nucleocapsid-specific T cells in acute self-limited hepatitis B. Hepatology 25:1022-7
Bertoletti, A; Southwood, S; Chesnut, R et al. (1997) Molecular features of the hepatitis B virus nucleocapsid T-cell epitope 18-27: interaction with HLA and T-cell receptor. Hepatology 26:1027-34
Bertoletti, A; D'Elios, M M; Boni, C et al. (1997) Different cytokine profiles of intraphepatic T cells in chronic hepatitis B and hepatitis C virus infections. Gastroenterology 112:193-9
Missale, G; Bertoni, R; Lamonaca, V et al. (1996) Different clinical behaviors of acute hepatitis C virus infection are associated with different vigor of the anti-viral cell-mediated immune response. J Clin Invest 98:706-14
Penna, A; Artini, M; Cavalli, A et al. (1996) Long-lasting memory T cell responses following self-limited acute hepatitis B. J Clin Invest 98:1185-94
Chisari, F V; Ferrari, C (1995) Hepatitis B virus immunopathology. Springer Semin Immunopathol 17:261-81
Chisari, F V; Ferrari, C (1995) Hepatitis B virus immunopathogenesis. Annu Rev Immunol 13:29-60

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