Induction of cytotoxic T lymphocyte responses against hepatitis delta virus antigens which protect against tumor formation in mice.
The cellular immune response is a crucial defense mechanism against hepatotropic viruses and in chronic viral hepatitis prevention. Moreover, hepatitis delta virus (HDV) immunogenicity may be an important component in the development of prophylactic and therapeutic vaccines. Therefore, we evaluated the immunogenicity of the small (HDAg) or large delta antigen (LHDAg) to be used as a DNA-based vaccine. We immunized different mouse haplotypes, determined cellular immune responses, and tested protection of animals against tumor formation using syngeneic tumor cells stably expressing the delta antigens. Both LHDAg and HDAg primed CD4+ and CD8+ T cell immunity against both forms of delta antigens. CD8+ T cell frequencies were about 1% and antigen-specific CD8+ T cells remained detectable directly ex vivo for at least 35 days post-injection. No anti-delta antibody responses could be detected despite multiple detection systems and varied immunization approaches. We observed protection against syngeneic tumor formation and growth in mice immunized with DNA plasmids encoding secreted or intracellular forms of HDAg and LHDAg but not with recombinant HDAg establishing the generation of significant cellular immunity in vivo. Both CD4+ and CD8+ T cells were required for antitumoral activity as determined by in vivo T cell depletion experiments. The results indicate that DNA-based immunization with genes encoding LHDAg and HDAg induces strong T cell responses and, therefore, is an attractive approach for the construction of therapeutic and prophylactic T cell vaccines against HDV.
Mauch
C
C
Department of Medicine II, University Hospital Freiburg, Hugstetter Strasse 55, D-79106, Freiburg, Germany.
Grimm
C
C
Meckel
S
S
Wands
J R
JR
Blum
H E
HE
Roggendorf
M
M
Geissler
M
M
D000818:Animals; D000914:Antibodies, Viral / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D003673:Defective Viruses / Q000276:immunology; D004353:Drug Evaluation, Preclinical; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006239:Haplotypes; D018963:Hepatitis Antigens / Q000276:immunology*; D003698:Hepatitis Delta Virus / Q000276:immunology*; D035923:Hepatitis delta Antigens; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D012515:Mast-Cell Sarcoma / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018482:Muscle, Skeletal / Q000166:cytology; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000637:transplantation; D019444:Vaccines, DNA / Q000276:immunology*; D014765:Viral Vaccines / Q000276:immunology*
D000914:Antibodies, Viral; D018963:Hepatitis Antigens; D035923:Hepatitis delta Antigens; D011994:Recombinant Proteins; D019444:Vaccines, DNA; D014765:Viral Vaccines; C442244:hepatitis delta virus large antigen; D007371:Interferon-gamma