Vaccination with protein-transduced dendritic cells elicits a sustained response to hepatitis C viral antigens.
OBJECTIVE
Professional antigen-presenting dendritic cells are capable of eliciting a vigorous antiviral response in naive T cells. The administration of antigen-loaded dendritic cells offers a potential approach to induce high-level immunity against hepatitis C virus.


METHODS
The dendritic cell population in mice was expanded in vivo by hydrodynamic delivery of naked DNA that encoded the secreted form of human fms-like tyrosine kinase 3 ligand. The CD11c-enriched dendritic cell population obtained from the spleen was transduced in vitro with recombinant hepatitis C virus core and nonstructural 5 proteins by using macromolecular-based protein delivery. Vaccine efficacy was assessed with a cytotoxic T-lymphocyte assay, cytokine enzyme-linked immunosorbent assays, and intracellular cytokine staining in vitro and by a tumor challenge model in vivo.


RESULTS
Relative to mice inoculated with nontransduced dendritic cells, splenocytes derived from mice immunized with either hepatitis C virus core-transduced or nonstructural 5-transduced dendritic cells showed 3- to 5-fold greater antigen-specific cytotoxic T lymphocyte activity. The CD4(+) T cells obtained from mice immunized with nonstructural 5-transduced dendritic cells produced interferon gamma, but not interleukin 4, when stimulated with nonstructural 5. In contrast, T cells derived from mice immunized with hepatitis C virus core-transduced dendritic cells produced neither interferon gamma nor interleukin 4 when stimulated with core protein. Mice vaccinated with nonstructural 5-transduced dendritic cells, but not a nonstructural 5-expressing plasmid, showed a sustained antiviral response to nonstructural 5 as evidenced by reduced growth of nonstructural 5-expressing tumor cells inoculated 10 weeks after vaccination.


CONCLUSIONS
These findings suggest that vaccination with protein-transduced dendritic cells may constitute an important antiviral strategy for hepatitis C virus.
The Liver Research Center, Department of Medicine, Rhode Island Hospital and Brown Medical School, Providence, 02903, USA.
Noriyoshi
N
Kuzushita
Stephen H
SH
Gregory
Nola A
NA
Monti
Rolf
R
Carlson
Stephan
S
Gehring
Jack R
JR
Wands
D000818:Animals; D000956:Antigens, Viral / Q000276:immunology*; D016207:Cytokines / Q000032:analysis; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology*; D006801:Humans; D007114:Immunization; D051379:Mice; D008807:Mice, Inbred BALB C; D014611:Vaccination; D014761:Viral Hepatitis Vaccines
D000956:Antigens, Viral; D016207:Cytokines; D014761:Viral Hepatitis Vaccines