Therapeutic Vaccines for Treatment of Chronic Hepatitis B Virus Infection

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The hepatitis B virus (HBV) causes acute and chronic liver disease throughout the world. The chronically infected patients with active liver disease carry a high risk of developing cirrhosis and hepatocellular carcinoma. Unfortunately, no effective therapy is currently available for these patients. The cellular immune response to HBV is thought to be responsible for viral clearance and disease pathogenesis during viral infections. The T cell response to HBV is vigorous, polyclonal, and multispecific in acutely infected patients who successfully clear the virus. In contrast, the T cell response is relatively weak and narrowly focused in chronically infected patients. Based on these observations, therapeutic enhancement of the T cell response to HBV has the potential to terminate chronic HBV infection.

HBV transgenic mice have been previously shown to be immunologically tolerant to hepatitis B surface antigen (HBsAg) at the T cell level and therefore represent a good animal model to develop immunotherapeutic approaches to terminate persistent infection. Using these transgenic animals it has been previously reported that adoptive transfer of HBV-specific cytotoxic T cells can abolish HBV gene expression and replication in hepatocytes by a noncytopathic mechanism mediated by inflammatory cytokines. These results suggest that viral clearance may be achievable in HBV chronically infected patients by a noncytopathic antiviral process if the toleralized HBV-specific CTLs can be adequately activated.

Others and we have recently shown that DNA immunization can induce HBsAg-specific antibody and CTL responses in mice and chimpanzees (ref 15, 17). Dendritic cell vaccination also produced strong CTL responses in mice. However, both immunization methods only achieved limited therapeutic effect in HBV transgenic mice. Apparently, more efficient strategies must be developed to generate a functionally effective CTL response in HBV transgenic animals and, by extension, in human HBV chronic patients to achieve therapeutic effects.

We have created HBV transgenic mice to test several novel methods for their ability to induce the CTL responses. Cytokines can function as immunologic adjuvants when administered during the development of an immune response. Coadministration of plasmids encoding cytokines has been reported to increase CTL responses to DNA vaccines. We use two techniques, in vivo electroporation and adenoviral vector, to deliver cytokines with HBV DNA vaccines to improve CTL production in the transgenic mice. The second approach is to apply engineered dendritic cells to present HBsAg or HBV DNA vaccines. Specifically, we will use adenoviral vector to modify cultured dendritic cells to express Th1 cytokines to further enhance their ability to induce the CTL responses. The last approach is to generate MHC/Ig-IL-2 bifunctional fusion proteins to target and activate HBV-specific CD8+ CTLs in vivo. The MHC/Ig dimer has been shown to specifically bind to antigen-specific CTLs. We will use DNA vaccines or dendritic cell vaccines to prime for induction of HBV-specific CTLs followed by treatment with MHC/Ig-IL-2 fusion protein. It is conceivable that the unique targeting ability of such MHC/Ig-IL-2 fusion protein can specifically direct IL-2 to stimulate and expand the populations of the vaccine-induced specific CTLs to achieve a therapeutic effect. Through all there efforts, we hope to develop a reliable method for inducing CTL responses in chronic HBV patients. Moreover, these novel methods for CTL induction may also find application for other infectious and malignant diseases.