Abstract

Hepatocellullar injury in hepatitis B virus (HBV) infection is believed to result from immune-mediated mechanisms related to host clearance of this noncytopathic virus. We have demonstrated that the immune response to the hepatitis B surface antigen (HBsAg) is regulated by immune response (Ir) genes that map to the murine MHC. High responder and nonresponder haplotypes have been identified. A correlation of HLA-DR phenotype and nonresponsiveness to the trial, HBsAg vaccine in human recipients has also been reported. We propose to comprehensively study the H-2 restricted, immune response to HBsAg in a murine model to evaluate: the influence of genetic and immunoregulatory factors, the cellular mechanisms and circumvention of genetic and induced HBsAg-nonresponsiveness, and definition of distinct epitopes on this complex antigen. Specific studies will include: (1) analysis of genetic mechanisms whereby the I-A and I-C subregions influence the immune response to distinct determinants on HBsAg; (2) the epitope specificity and I-region restriction of HBsAg-specific functional T cell subsets; (3) the use of chemically synthesized peptide analogues of HBsAg to study the nature of the antigenic epitopes recognized by T cell functional subsets and B cells; (4) examination of mechanisms of HBsAg nonresponsiveness and strategies to bypass it; and (5) analysis of the influence of HLA-linked genes on the human immune response to HBsAg immunization. In view of the extensive preliminary data, the availability of purified HBsAg preparations and synthetic peptide analogues, and the experience of the co-investigators in developing HBsAg-specific, serological and cellular assay systems, this model offers a unique opportunity to study the regulation of the immune response to HBsAg, a pathogenetically relevant, multideterminant, Ir-restricted antigen. This system is expected to provide critical information applicable to HBsAg vaccine strategies, the understanding of pathogenetic mechanisms in HBV infection as well as basic information relating to mechanisms of Ir gene function.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Modified Research Career Development Award (K04)
Project #
5K04AI000585-02
Application #
3070698
Study Section
Immunobiology Study Section (IMB)
Project Start
1984-09-30
Project End
1989-08-31
Budget Start
1985-09-01
Budget End
1986-08-31
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
Scripps Research Institute
Department
Type
DUNS #
City
San Diego
State
CA
Country
United States
Zip Code
92037

  Publications

Milich, D R (1991) Immune response to hepatitis B virus proteins: relevance of the murine model. Semin Liver Dis 11:93-112
Milich, D R; Jones, J E; McLachlan, A et al. (1990) Importance of subtype in the immune response to the pre-S(2) region of the hepatitis B surface antigen. II. Synthetic Pre-S(2) immunogen. J Immunol 144:3544-51
Raney, A K; Milich, D R; Easton, A J et al. (1990) Differentiation-specific transcriptional regulation of the hepatitis B virus large surface antigen gene in human hepatoma cell lines. J Virol 64:2360-8
Milich, D R; Hughes, J L; McLachlan, A et al. (1990) Importance of subtype in the immune response to the pre-S(2) region of the hepatitis B surface antigen. I. T cell fine specificity. J Immunol 144:3535-43
Milich, D R (1989) Synthetic T and B cell recognition sites: implications for vaccine development. Adv Immunol 45:195-282
Raney, A K; Milich, D R; McLachlan, A (1989) Characterization of hepatitis B virus major surface antigen gene transcriptional regulatory elements in differentiated hepatoma cell lines. J Virol 63:3919-25
Raney, A K; Milich, D R; Hughes, J L et al. (1989) Retroviral-mediated transfer and expression of hepatitis B e antigen in human primary skin fibroblasts and Epstein-Barr virus-transformed B lymphocytes. Virology 168:31-9
Milich, D R; Jones, J E; McLachlan, A et al. (1989) Distinction between immunogenicity and tolerogenicity among HBcAg T cell determinants. Influence of peptide-MHC interaction. J Immunol 143:3148-56
Milich, D R; Hughes, J L; Houghten, R et al. (1989) Functional identification of agretopic and epitopic residues within an HBcAg T cell determinant. J Immunol 143:3141-7
Milich, D R (1989) Molecular and genetic aspects of the immune responses to hepatitis B viral antigens. Adv Exp Med Biol 257:115-33

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