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Critical components of a DNA fusion vaccine able to induce protective cytotoxic T cells against a single epitope of a tumor antigen

Critical components of a DNA fusion vaccine able to induce protective cytotoxic T cells against a single epitope of a tumor antigen
Critical components of a DNA fusion vaccine able to induce protective cytotoxic T cells against a single epitope of a tumor antigen
DNA vaccines can activate immunity against tumor Ags expressed as MHC class I-associated peptides. However, priming of CD8+ CTL against weak tumor Ags may require adjuvant molecules. We have used a pathogen-derived sequence from tetanus toxin (fragment C (FrC)) fused to tumor Ag sequences to promote Ab and CD4+ T cell responses. For induction of CD8+ T cell responses, the FrC sequence has been engineered to remove potentially competitive MHC class I-binding epitopes and to improve presentation of tumor epitopes.
The colon carcinoma CT26 expresses an endogenous retroviral gene product, gp70, containing a known H2-Ld-restricted epitope (AH1). A DNA vaccine encoding gp70 alone was a poor inducer of CTL, and performance was not significantly improved by fusion of full-length FrC. However, use of a minimized domain of FrC, with the AH1 sequence fused to the 3' position, led to rapid induction of high levels of CTL. IFN-?-producing epitope-specific CTL were detectable ex vivo and these killed CT26 targets in vitro. The single epitope vaccine was more effective than GM-CSF-transfected CT26 tumor cells in inducing an AH1-specific CTL response and equally effective in providing protection against tumor challenge.
Levels of AH1-specific CTL in vivo were increased following injection of tumor cells, and CTL expanded in vitro were able to kill CT26 cells in tumor bearers. Pre-existing immunity to tetanus toxoid had no effect on the induction of AH1-specific CTL. These data demonstrate the power of epitope-specific CTL against tumor cells and illustrate a strategy for priming immunity via a dual component DNA vaccine.
0022-1767
3908-3913
Rice, Jason
d58d4fcd-8dc0-4599-bf96-62323d579227
Buchan, Sarah
9ade187d-f127-45de-ad90-9d544d64718a
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c
Rice, Jason
d58d4fcd-8dc0-4599-bf96-62323d579227
Buchan, Sarah
9ade187d-f127-45de-ad90-9d544d64718a
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c

Rice, Jason, Buchan, Sarah and Stevenson, Freda K. (2002) Critical components of a DNA fusion vaccine able to induce protective cytotoxic T cells against a single epitope of a tumor antigen. Journal of Immunology, 169 (7), 3908-3913.

Record type: Article

Abstract

DNA vaccines can activate immunity against tumor Ags expressed as MHC class I-associated peptides. However, priming of CD8+ CTL against weak tumor Ags may require adjuvant molecules. We have used a pathogen-derived sequence from tetanus toxin (fragment C (FrC)) fused to tumor Ag sequences to promote Ab and CD4+ T cell responses. For induction of CD8+ T cell responses, the FrC sequence has been engineered to remove potentially competitive MHC class I-binding epitopes and to improve presentation of tumor epitopes.
The colon carcinoma CT26 expresses an endogenous retroviral gene product, gp70, containing a known H2-Ld-restricted epitope (AH1). A DNA vaccine encoding gp70 alone was a poor inducer of CTL, and performance was not significantly improved by fusion of full-length FrC. However, use of a minimized domain of FrC, with the AH1 sequence fused to the 3' position, led to rapid induction of high levels of CTL. IFN-?-producing epitope-specific CTL were detectable ex vivo and these killed CT26 targets in vitro. The single epitope vaccine was more effective than GM-CSF-transfected CT26 tumor cells in inducing an AH1-specific CTL response and equally effective in providing protection against tumor challenge.
Levels of AH1-specific CTL in vivo were increased following injection of tumor cells, and CTL expanded in vitro were able to kill CT26 cells in tumor bearers. Pre-existing immunity to tetanus toxoid had no effect on the induction of AH1-specific CTL. These data demonstrate the power of epitope-specific CTL against tumor cells and illustrate a strategy for priming immunity via a dual component DNA vaccine.

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Published date: 1 October 2002

Identifiers

Local EPrints ID: 26570
URI: http://eprints.soton.ac.uk/id/eprint/26570
ISSN: 0022-1767
PURE UUID: 7a063961-f507-49ed-9ff9-0ac338a70f16
ORCID for Freda K. Stevenson: ORCID iD orcid.org/0000-0002-0933-5021

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Date deposited: 20 Apr 2006
Last modified: 06 Jun 2018 13:01

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