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A novel transgenic mouse model for immunological evaluation of carcinoembryonic antigen–based DNA minigene vaccines
He Zhou, … , Rong Xiang, Ralph A. Reisfeld
He Zhou, … , Rong Xiang, Ralph A. Reisfeld
Published June 15, 2004
Citation Information: J Clin Invest. 2004;113(12):1792-1798. https://doi.org/10.1172/JCI21107.
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Article

A novel transgenic mouse model for immunological evaluation of carcinoembryonic antigen–based DNA minigene vaccines

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Abstract

A lack of relevant animal models has hampered preclinical screening and critical evaluation of the efficacy of human vaccines in vivo. Carcinoembryonic antigen–A2Kb (CEA–A2Kb) double transgenic mice provide a biologically relevant model for preclinical screening and critical evaluation of human CEA vaccine efficacy in vivo, particularly because such animals are peripherally tolerant of CEA. We established the utility of this model by demonstrating that an oral DNA minigene vaccine induces effective HLA-A2–restricted, CEA-specific antitumor CTL responses. This finding is supported by three lines of evidence: (a) an effective HLA-A2–restricted, CEA691-specific CTL response; (b) specific in vitro killing of CEA-A2Kb transduced MC-38 colon carcinoma cells; and (c) protective immunity induced in vaccinated mice against challenges of these tumor cells. Importantly, peripheral T cell tolerance against CEA in CEA-A2Kb double transgenic mice was broken by the CEA691 (IMIGVLVGV) minigene vaccine. In conclusion, CEA-A2Kb double transgenic mice were demonstrated to be good candidates for in vivo testing of human CEA–based vaccines. This result suggests a potential for these vaccines in future human vaccine development. The feasibility of using nonmutated self-antigens as targets for therapeutic vaccinations was indicated, provided that such antigens are presented in an immunogenic context; that is, as a DNA minigene in a bacterial carrier system.

Authors

He Zhou, Yunping Luo, Masato Mizutani, Noriko Mizutani, Jürgen C. Becker, F. James Primus, Rong Xiang, Ralph A. Reisfeld

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Figure 5

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The DNA minigene vaccine pHI-691 induces HLA-A2–restricted killing of MC...
The DNA minigene vaccine pHI-691 induces HLA-A2–restricted killing of MC-38-CEA-A2Kb cells. (A) Surface expression of HLA-A2 and CEA by MC-38-CEA-A2Kb (left) and MC-38-CEA (right). Tumor cells were washed and incubated with isotype control Ab (thin dashed lines), anti–HLA-A2 (thin solid lines), or anti-CEA (heavy solid lines) and stained with PE-conjugated (Fab′)2 of goat anti–mouse Ig Ab. Groups of C57BL/6-CEA-A2Kb mice (n = 4) were immunized three times at 2-week intervals with attenuated S. typhimurium harboring the vectors indicated. Mice were sacrificed 2 weeks after the last immunization, and isolated splenocytes were stimulated with irradiated MC-38-CEA-A2Kb cells for 5 days. Thereafter, cytotoxicity assays were performed with (B) MC-38-CEA-A2Kb or (C) MC-38-CEA as target cells. max, maximum.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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