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  • Acquired Diseases
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IL-12 plasmid-enhanced DNA vaccination against carcinoembryonic antigen (CEA) studied in immune-gene knockout mice

Gene Therapy volume 7, pages 1527–1535 (2000)Cite this article

Abstract

Intramuscular (i.m.) injection of a plasmid encoding human carcinoembryonic antigen (CEA) elicited immunity against transplanted syngeneic (C57BL/6) CEA-positive Lewis lung carcinoma (CEA/LLC) cells, but tumors still appeared in all mice. In wild-type mice, coinjection of an IL-12 plasmid markedly enhanced anti-CEA humoral, T-helper-1 and cytotoxic T lymphocyte (CTL) responses, and resistance to a CEA/LLC tumor challenge such that 80% of mice remained tumor free. Injection of the IL-12 plasmid alone was not protective. To analyze immune requirements, we immunized gene knockout (KO) mice of C57BL/6 background, deficient in either CD3, CD4, CD8, interferon γ (IFNγ), perforin or Fas ligand (FasL). Only CD3+mice expressing both CD4 and CD8, which appear equally important, as well as IFNγ and perforin, could fully resist a tumor challenge. IL-12 stimulated CTL activity, which was strictly CD3/CD8/perforin-dependent. FasL-KO mice had normal CTL activity and tumor resistance, indicating that only the perforin lytic pathway was involved. CD4-KO and IFNγ-KO mice still generated CTLs. CEA-stimulated IFNγ production occurred in both CD4- or CD8-KO mice and in both cases was augmented by IL-12. In IFNγ-KO mice, IL-12 still enhanced anti-CEA antibody production but only moderately restored impaired DTH and tumor resistance. We conclude that the immune requirements for tumor rejection are stringent, involving multiple mechanisms which are all enhanced by IL-12.

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Acknowledgements

The thank Vical Inc, San Diego, California, for kindly providing the VR1255 vector used in these experiments. We thank Dr Abraham Fuks (McGill University, Montreal, Canada) and Dr Serge Jothy (Sunnybrook Hospital, Toronto, Ontario, Canada) for kindly providing reagents and cell lines, Dr Fawaz Halwani (McGill University, Montreal, Canada) for assistance with FACS analyses, and Dr Fu Hu (Montreal General Hospital, Montreal, Canada) for assistance with statistical analyses. This study was funded by the Fraser Fund (Royal Victoria Hospital, Montreal, Canada). Keli Song was supported in part by Royal Victoria Hospital Research Institute Fellowship.

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  1. Department of Pathology, McGill University, 3775 University Street, Room B13, Montreal, Quebec, H3A 2B4, Canada

    K Song, Y Chang & G J Prud'homme

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Song, K., Chang, Y. & Prud'homme, G. IL-12 plasmid-enhanced DNA vaccination against carcinoembryonic antigen (CEA) studied in immune-gene knockout mice. Gene Ther 7, 1527–1535 (2000). https://doi.org/10.1038/sj.gt.3301274

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