Shanmuganathan, S; (1998) The woodchuck as an animal model for the study of the immune response in hepaDNA viral infection. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The American woodchuck (Marmota monax) is naturally infected in the wild with a virus called WHV which is similar to HBV. WHV infection causes acute and chronic hepatitis eventually leading to HCC in the majority of cases; the hepatitis is thought to be mediated by the same immune mechanisms involved in HBV infection of humans although this is not yet proven. These similarities make the woodchuck an appropriate model for the study of HBV immunopathogenesis. Lack of information on the woodchuck immune response led to the development of T cell proliferative assays which were initially attempted using conditions suitable for culturing human PBLs. The conditions and kinetics of the T cell response to mitogens was found to differ from humans and other sciurid rodents. This technique was used to investigate the T cell responses to WHV nucleocapsid peptides; an immunodominant epitope was identified in 5 out of 12 chronically infected animals. In addition to devising an assay to assess T cell responses the crossreactivity that exists between WHeAg and HBeAg enabled employment of a commercial assay to quantify WHeAg levels. Four parameters could now be used to monitor the effects of treatments- WHV DNA, WHeAg, T cell responses and GGT levels. The treatments attempted in this study targeted mainly the cellular arm of the immune response ranging from the use of chemical immunomodulators, such as tucaresol and MPC-866, to the infusion of T cells. T cell adoptive transfer and IL-12 were new treatments tried for the first time in this model. IL-12 was found to increase the proliferative response of woodchuck PBLs with and without PHA in vitro. The woodchuck can be used to further investigate the usefulness of these and other putative therapies of HBV infection.

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