DNA fusion gene vaccination mobilizes effective anti-leukemic cytotoxic T lymphocytes from a tolerized repertoire.
The majority of known human tumor-associated antigens derive from non-mutated self proteins. T cell tolerance, essential to prevent autoimmunity, must therefore be cautiously circumvented to generate cytotoxic T cell responses against these targets. Our strategy uses DNA fusion vaccines to activate high levels of peptide-specific CTL. Key foreign sequences from tetanus toxin activate tolerance-breaking CD4(+) T cell help. Candidate MHC class I-binding tumor peptide sequences are fused to the C terminus for optimal processing and presentation. To model performance against a leukemia-associated antigen in a tolerized setting, we constructed a fusion vaccine encoding an immunodominant CTL epitope derived from Friend murine leukemia virus gag protein (FMuLV(gag)) and vaccinated tolerant FMuLV(gag)-transgenic (gag-Tg) mice. Vaccination with the construct induced epitope-specific IFN-gamma-producing CD8(+) T cells in normal and gag-Tg mice. The frequency and avidity of activated cells were reduced in gag-Tg mice, and no autoimmune injury resulted. However, these CD8(+) T cells did exhibit gag-specific cytotoxicity in vitro and in vivo. Also, epitope-specific CTL killed FBL-3 leukemia cells expressing endogenous FMuLV(gag) antigen and protected against leukemia challenge in vivo. These results demonstrate a simple strategy to engage anti-microbial T cell help to activate epitope-specific polyclonal CD8(+) T cell responses from a residual tolerized repertoire.
Rice
Jason
J
Molecular Immunology Group, Cancer Sciences Division, University of Southampton School of Medicine, Southampton, UK. J.Rice@soton.ac.uk <J.Rice@soton.ac.uk>
Dossett
Michelle L
ML
Ohlén
Claes
C
Buchan
Sarah L
SL
Kendall
Timothy J
TJ
Dunn
Stuart N
SN
Stevenson
Freda K
FK
Greenberg
Philip D
PD
D000818:Animals; D019677:Artificial Gene Fusion; D015551:Autoimmunity; D019496:Cancer Vaccines / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte; D005622:Friend murine leukemia virus / Q000276:immunology; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance; D007938:Leukemia / Q000276:immunology* / Q000628:therapy; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013950:Thymus Gland / Q000378:metabolism; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology*
D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D019444:Vaccines, DNA