| First Author | Rice J | Year | 2008 |
| Journal | Eur J Immunol | Volume | 38 |
| Issue | 8 | Pages | 2118-30 |
| PubMed ID | 18624299 | Mgi Jnum | J:140422 |
| Mgi Id | MGI:3813766 | Doi | 10.1002/eji.200838213 |
| Citation | Rice J, et al. (2008) DNA fusion gene vaccination mobilizes effective anti-leukemic cytotoxic T lymphocytes from a tolerized repertoire. Eur J Immunol 38(8):2118-30 |
| abstractText | 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. |
