Designing a therapeutic hepatitis B vaccine to circumvent immune tolerance.

An effective prophylactic hepatitis B virus (HBV) vaccine has long been available but is ineffective for chronic infection. The primary cause of chronic hepatitis B (CHB) and greatest impediment for a therapeutic vaccine is the direct and indirect effects of immune tolerance to HBV antigens. The resulting defective CD4+/CD8+ T cell response, poor cytokine production, insufficient neutralizing antibody (nAb) and poor response to HBsAg vaccination characterize CHB infection. The objective of this study was to develop virus-like-particles (VLPs) that elicit nAb to prevent viral spread and prime CD4+/CD8+ T cells to eradicate intracellular HBV. Eight neutralizing B cell epitopes from the envelope PreS1 region were consolidated onto a species-variant of the HBV core protein, the woodchuck hepatitis core antigen (WHcAg). PreS1-specific B cell epitopes were chosen because of preferential expression on HBV virions. Because WHcAg and HBcAg are not crossreactive at the B cell level and only partially cross-reactive at the CD4+/CD8+ T cell level, CD4+ T cells specific for WHcAg-unique T cell sites can provide cognate T-B cell help for anti-PreS1 Ab production that is not curtailed by immune tolerance. Immunization of immune tolerant HBV transgenic (Tg) mice with PreS1-WHc VLPs elicited levels of high titer anti-PreS1 nAbs equivalent to wildtype mice. Passive transfer of PreS1 nAbs into human-liver chimeric mice prevented acute infection and cleared serum HBV from mice previously infected with HBV in a model of CHB. At the T cell level, PreS1-WHc VLPs and hybrid WHcAg/HBcAg DNA immunogens elicited HBcAg-specific CD4+ Th and CD8+ CTL responses.

Halothane-induced changes in neuronal activity of cells of the nucleus reticularis gigantocellularis of the cat.

The ability of 0.5% and 1.0% halothane to suppress neuronal activity of cells in the nucleus reticularis gigantocellularis (NRGC) was studied in decerebrate cats. These drug effects were examined in order to substantiate further the potential involvement of the NRGC in the modulation of transmission of pain information. Only cells of the NRGC, which were excited exclusively by electrical stimulation of A-delta fibers in the superficial radial nerve, were studied. Both concentrations of halothane caused a significant, dose-dependent reduction of spontaneous and evoked activity of all cells studied. These findings correlate well with previous reports of other anesthetics suppressing NRGC activity. In light of the selective depression by anesthetics and narcotic analgesics of spinal cord dorsal horn cells associated with noxious stimuli, these findings, when combined with anatomic, physiologic, and behavioral studies of NRGC, provide further evidence of the involvement of NRGC in the signaling of noxious stimuli and the analgesic effects of halothane exerted at this site.