Chronic viral hepatitis is a major cause of morbidity and mortality worldwide, and in this family of diseases the immune system is believed to be responsible for the majority of the tissue damage. Animal models of acute immuno-inflammatory liver damage abound, but there is a need for a model that reproduces the key features of chronic viral hepatitis: liver injury, fibrosis, immune failure, and persistence of the pathogen. We have developed a promising new model, in which persistent infection with an Adeno-Associated Virus vector directs expression of the target antigen to hepatocytes for at least 8 months, while exogenous T cells cause tissue damage and activate stellate cells. Prolonged co-existence of the antigen and the T cells leads to T cell dysfunction. Although this model is based on a replication- defective vector, it is an excellent vehicle to study the interactions of T cells with antigen expressed exclusively in hepatocytes. Unlike murine hepatotropic viruses, the vector model in unlikely to entail adaptations to disable liver immunity;thus we can study the immune response to hepatocellular antigens in isolation. Using this model, in Aim 1 we will test the mechanism of hepatocellular injury during acute and chronic immune inflammation.
In Aim 2, we will test the mechanisms of stellate cell activation.
In Aim 3 we will test the hypothesis that vector persistence is due to the lack of CD4+ T cell activation, because of a lack of cross-priming.
In Specific Aim 4, we will induce chronic relapsing hepatitis, and test whether repeated cycles of inflammation lead to sustained stellate cell activation with liver fibrosis. A model that reproduces chronic liver damage, stellate cell activation and immune dysfunction will be most valuable in generating paradigms useful for mechanistic investigations of the mechanism of action of existing anti-viral therapy, and for the rational design of new therapies. Relevance to public health: The immune system is important in fighting against hepatitis viruses, but in the process immune cells cause damage to the liver. We have developed an entirely new mouse model that will make it possible to distinguish the pathways of immune damage from those that fight invaders. This will open the way to new kinds of treatment for hepatitis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Doo, Edward
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Seattle Biomedical Research Institute
United States
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Crispe, Ian N (2014) Immune tolerance in liver disease. Hepatology 60:2109-17
Crispe, Ian Nicholas (2011) Liver antigen-presenting cells. J Hepatol 54:357-65
Ebrahimkhani, Mohammad R; Mohar, Isaac; Crispe, Ian N (2011) Cross-presentation of antigen by diverse subsets of murine liver cells. Hepatology 54:1379-87
Spahn, Jessica; Pierce, Robert H; Crispe, Ian N (2011) Ineffective CD8(+) T-cell immunity to adeno-associated virus can result in prolonged liver injury and fibrogenesis. Am J Pathol 179:2370-81
Wuensch, Sherry A; Spahn, Jessica; Crispe, Ian N (2010) Direct, help-independent priming of CD8+ T cells by adeno-associated virus-transduced hepatocytes. Hepatology 52:1068-77
Giannandrea, Matthew; Pierce, Robert H; Crispe, Ian Nicholas (2009) Indirect action of tumor necrosis factor-alpha in liver injury during the CD8+ T cell response to an adeno-associated virus vector in mice. Hepatology 49:2010-20