DNA fusion gene vaccination mobilizes effective anti-leukemic cytotoxic T lymphocytes from a tolerized repertoire
Authors: Rice, J., Dossett, M.L., Öhlén, C., Buchan, S.L., Kendall, T.J., Dunn, S.N., Stevenson, F.K. and Greenberg, P.D.
Journal: European Journal of Immunology
Volume: 38
Issue: 8
Pages: 2118-2130
ISSN: 0014-2980
DOI: 10.1002/eji.200838213
Abstract:The majority of known human tumor-associated antigens, derive from non-mutated self proteins. T cell tolerance, essential to prevent autoimmunnity 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 (FMuLVgag) and vaccinated tolerant FMuLVgag-transgenic (gag-Tg) mice. Vaccination with the construct induced epitopespecific IFN-γ-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 FMuLVgag 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. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Source: Scopus
DNA fusion gene vaccination mobilizes effective anti-leukemic cytotoxic T lymphocytes from a tolerized repertoire.
Authors: Rice, J., Dossett, M.L., Ohlén, C., Buchan, S.L., Kendall, T.J., Dunn, S.N., Stevenson, F.K. and Greenberg, P.D.
Journal: Eur J Immunol
Volume: 38
Issue: 8
Pages: 2118-2130
ISSN: 0014-2980
DOI: 10.1002/eji.200838213
Abstract: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.
Source: PubMed
DNA fusion gene vaccination mobilizes effective anti-leukemic cytotoxic T lymphocytes from a tolerized repertoire
Authors: Rice, J., Dossett, M.L., Oehlen, C., Buchan, S.L., Kendall, T.J., Dunn, S.N., Stevenson, F.K. and Greenberg, P.D.
Journal: EUROPEAN JOURNAL OF IMMUNOLOGY
Volume: 38
Issue: 8
Pages: 2118-2130
ISSN: 0014-2980
DOI: 10.1002/eji.200838213
Source: Web of Science (Lite)
DNA fusion gene vaccination mobilizes effective anti-leukemic cytotoxic T lymphocytes from a tolerized repertoire.
Authors: Rice, J., Dossett, M.L., Ohlén, C., Buchan, S.L., Kendall, T.J., Dunn, S.N., Stevenson, F.K. and Greenberg, P.D.
Journal: European journal of immunology
Volume: 38
Issue: 8
Pages: 2118-2130
eISSN: 1521-4141
ISSN: 0014-2980
DOI: 10.1002/eji.200838213
Abstract: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.
Source: Europe PubMed Central