# PATHOGENESIS OF LIVER DISEASE IN HEPATITIS

> **NIH NIH R01** · SCRIPPS CLINIC AND RESEARCH FOUNDATION · 1987 · $248,558

## Abstract

The mechanism(s) responsible for hepatocellular injury and malignant
transformation following hepatitis B virus (HBV) infection are entirely
unknown.  Since HBV infection is not directly cytopathic for hepatocytes,
the dominant current hypothesis proposes that the cellular immune response
destroys infected hepatocytes that express one or more virus encoded
antigens their surface in the context of autologous HLA determinants.  This
hypothesis has not been tested due to the unavailability of human target
cells that co-express the appropriate viral and histocompatibility antigens
that are required for definitive study of antigen specific, HLA restricted
T cell mediated cytotoxicity in this disease.

Our long term programmatic objective is to test the above hypothesis.
Thus, we have developed the technology necessary to produce stable, high
level, expression of HBV encoded antigens at high efficiency in primary
human cell lines of defined HLA phenotype.  Using a unique family of
recombinant amphotropic retroviruses containing a postitive selectable
marker (neo) plus the coding regions for all the known hepatitis B virus
antigens, drug resistant lines of primary human fibroblasts that synthesize
and secrete native HBsAg have recently been produced.  The gene product is
authentic in terms of buoyant density, morphology, mean diameter,
polypeptide composition, and antigenicity.  This illustrates that the
constructs faithfully represent the native coding regions and it suggests
that they will direct the synthesis by human target cells of native HBV
encoded antigens.  Antigens so produced and expressed should be
recognizable by lymphocytes sensitized in vivo during natural HBV infection.

We have also created the organizational framework necessary for the
identification and recruitment of large numbers of patients with acute and
chronic hepatitis B virus infection and the collection, processing and
storage of specimens for immunologic analysis.  To date nearly 50 patient
volunteers have entered our program and we are adding new subjects at a
rate of about one each week.  At this rate between 200-250 subjects will
constitute the study group for these experiments.

Using these tools we will analyze the cellular immune response to each of
the HBV encoded antigens in the context of self HLA.  These results will be
correlated with clinical and biochemical parameters of disease activity to
examine the possibility of a causal relationship between the two.  The
effector cell(s) will be identified and the important regulatory events
that may influence the quality and magnitude of the cellular immune
response will be examined.

## Key facts

- **NIH application ID:** 3129464
- **Project number:** 5R01AI020001-05
- **Recipient organization:** SCRIPPS CLINIC AND RESEARCH FOUNDATION
- **Principal Investigator:** FRANCIS VINCENT CHISARI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1987
- **Award amount:** $248,558
- **Award type:** 5
- **Project period:** 1983-07-01 → 1989-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3129464

## Citation

> US National Institutes of Health, RePORTER application 3129464, PATHOGENESIS OF LIVER DISEASE IN HEPATITIS (5R01AI020001-05). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3129464. Licensed CC0.

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