Functional Aspects of Intrahepatic Hepatitis B Virus-specific T Cells Induced by Therapeutic DNA Vaccination
| Autor: | Anette Brass, Gustaf Ahlén, David R. Milich, Matti Sällberg, Lars Frelin |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Hepatitis B virus
T-Lymphocytes Gene Expression Mice Transgenic Biology medicine.disease_cause DNA vaccination Mice Hepatitis B Chronic Drug Discovery medicine Vaccines DNA Genetics Animals Humans Hepatitis B Vaccines Hepatitis B e Antigens Hepatitis B Antibodies Molecular Biology Cell Proliferation Pharmacology Vaccination virus diseases Hepatitis B medicine.disease Virology Hepatitis B Core Antigens Interleukin-12 digestive system diseases HBcAg Electroporation HBeAg Viral replication Liver Immunology Interleukin 12 Hepatocytes Molecular Medicine Original Article Plasmids |
| Zdroj: | Molecular Therapy |
| ISSN: | 1525-0016 |
| DOI: | 10.1038/mt.2014.233 |
| Popis: | Current therapies for the hepatitis B virus (HBV), a major cause of severe liver disease, suppress viral replication but replication rebounds if therapy is withdrawn. It is widely accepted that immune activation is needed to control replication off-therapy. To specifically activate T cells crossreactive between the hepatitis B core and e antigens (HBcAg/HBeAg) in chronically infected patients, we developed a therapeutic vaccine candidate. The vaccine encompass codon-optimized HBcAg and IL-12 expressing plasmids delivered using targeted high-pressure injection combined with in vivo electroporation. One dose of the vaccine primed a B-cell-independent polyfunctional T-cell response, in wild-type, and in HBeAg-transgenic mice with an impaired ability to respond to HBc/eAg. The response peaked at 2 weeks and contracted at week 6 after vaccination. Coadministration of IL-12 improved antibody levels, and T-cell expansion and functionality. The vaccine primed T cells that, 2 weeks after a single dose, cleared hepatocytes transiently expressing HBcAg in vaccinated wild-type and HBeAg-transgenic mice. However, 4 weeks later, these functional responses were lost. Booster doses after 8–12 weeks effectively restored function and expansion of the rapidly contracting T cells. Thus, this vaccine strategy primes functional HBcAg-specific T cells in a host with dysfunctional response to HBV. |
| Databáze: | OpenAIRE |
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