DENDRITIC CELL IMMUNIZATION BREAKS CYTOTOXIC T-LYMPHOCYTE TOLERANCE IN HEPATITIS-B VIRUS TRANSGENIC MICE

Hepatitis B virus (HBV) transgenic mice that are immunologically toler ant to HBV-encoded Ags represent a model of chronic HEV infection suit able for the development of therapeutic immunization strategies before testing in humans. Five Lineages of HRV transgenic mice were immunize d with plasmid DNA that encodes hepatitis B surface Ag (HBsAg) or with cytokine-activated bone marrow-derived dendritic cells (DCs) in an at tempt to break tolerance to HBsAg at the B and T cell levels. DNA immu nization stimulated an Ab response but not a cytotoxic T lymphocyte re sponse to HBsAg in two of the five transgenic lineages studied, In con trast, infusion of activated transgenic or nontransgenic DCs stimulate d a splenic CTL response in all three transgenic lineages immunized in this manner at precursor frequencies comparable to those in nontransg enic mice, indicating that DC function, is normal, and HBsAg-specific CTLs are present but functionally silent in these transgenic animals. Importantly, none of the animals developed hepatitis or displayed supp ressed viral gene expression or replication following either DNA immun ization or DC administration even in the presence of anti-hepatitis B surface (HBs) Abs and HBs-specific CTLs, These results indicate that A g presentation by cytokine-activated DCs can break tolerance and trigg er an anti-viral CTL response in HRV transgenic mice, and they suggest that this strategy is more efficient than DNA immunization in this se tting, Nonetheless, more efficient immunization strategies are needed to stimulate an immune response of sufficient quality and magnitude to achieve an immunotherapeutic antiviral effect.