Ongoing Murine T1 or T2 Immune Responses to the Hepatitis B Surface Antigen Are Excluded from the Liver that Expresses Transgene-Encoded Hepatitis B Surface Antigen

Abstract

Different protein- or DNA-based vaccination techniques are available that prime potent humoral and cellular, T1 or T2 immune responses to the hepatitis B surface Ag (HBsAg) in mice. T1 and T2 are immune responses with isotype profile indicating Th1 and Th2 immunoregulation. We tested whether HBsAg-specific immune responses can be established in transgenic mice that express HBsAg in the liver (HBs-tg mice) using either these different vaccination techniques or an adoptive transfer system. HBsAg-specific responses could not be primed in HBs-tg mice with the established, potent vaccine delivery techniques. In contrast, adoptive transfers of T1- and T2-type HBsAg-immune spleen cells into congenic HBs-tg hosts (that were not conditioned by pretreatment) suppressed HBsAg antigenemia and gave rise to HBsAg-specific serum Ab titers. The establishment of continuously rising anti-HBsAg serum Ab levels with alternative isotype profiles (reflecting T1 or T2 polarization) in transplanted HBs-tg hosts required donor CD4+ T cell-dependent restimulation of adoptively transferred immune cells by transgene-derived HBsAg. Injections of HBsAg-specific Abs into HBs-tg mice did not establish stable humoral immunity. The expanding T1 or T2 immune responses to HBsAg in HBs-tg hosts did not suppress transgene-directed HBsAg expression in the liver and did not induce liver injury. In addition to priming functional antiviral effector cells, the conditioning of the liver microenvironment to enable delivery of antiviral effector functions to this organ are therefore critical for effective antiviral defense. A major challenge in the development of a therapeutic vaccine against chronic hepatitis B or C virus infection is thus the efficient targeting of specifically induced immune effector specificities to the liver.

IL-20 Receptor 2 Signaling Down-Regulates Antigen-Specific T Cell Responses

“…rIL-19 enhances the induction of Th2 cytokines in a murine asthma model (14,39). In vivo, a shift of Th1 to Th2 answers results in switching of the IgG isotype to higher IgG1/IgG2a ratios (27) ϩ/Ϫ T cell cultures was not sufficient to increase the production of IL-4 and IL-10 above the detection limit of the ELISA. The second reason could be that IL-24 or IL-19, which signals via IL-20R type I, might be responsible for the repression of T cells.…”

“…The IgG2a/IgG1 ratio was not changed in knockout mice when compared with vaccinated wild-type littermates (data not shown). With Th2 (i.d., gene gun)-directed vaccination strategies (27) that generate high amounts of IgG1 relative to IgG2a, comparable IgG2a/IgG1 serum responses were mounted in both mouse strains (BALB/c background). Thus, the immune system is not shifted toward a more Th1-like Ab isoprofile (i.e., higher IgG2a/ IgG1 ratio) in IL-20R2 Ϫ/Ϫ mice under noninflammatory conditions used in this study.…”

“…We therefore tested in vivo whether the Ab response to Ag is shifted toward a Th1-like isotype response in knockout mice. During Th2-like immune reactions, a lower IgG2a/IgG1 isotype ratio of Ag-specific Abs is generated than in Th1-polarized immune answers (27). The specific Ab response to HBsAg after vaccination with pCI/S was analyzed in IL-20R2 Ϫ/Ϫ and IL-20R2 ϩ/ϩ littermates.…”

“…pCI/S. The Ag sequence in the resulting pCI/S and pCI/OVA vectors is under the control of the CMV immediate early promoter (27).…”

“…nucleic acid immunization was achieved by injecting 50 g (1 g/ml) of plasmid DNA into each tibialis muscle, as described previously (28). Intradermal injection of 2 g of particle-loaded DNA with the Helios gene gun system (Bio-Rad) was performed as described (27). Mice were vaccinated once and analyzed at day 12.…”