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  • Acquired Diseases
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Interleukin-18 gene transfer increases antitumor effects of suicide gene therapy through efficient induction of antitumor immunity

Gene Therapy volume 7, pages 1672–1679 (2000)Cite this article

Abstract

To increase the antitumor effects of cytosine deaminase (AdCD) gene therapy and induce more potent antitumor immunity, Th1 cytokine interleukin-18 encoded adenovirus (AdIL18) was combined with adenovirus encoding CD (AdCD) for the therapy of established murine B16 melanoma. Combination therapy of the tumor-bearing mice with AdIL18 and AdCD/5FC inhibited the growth of the subcutaneous B16 tumors more significantly, compared with AdIL18 or AdCD/5FC alone. In vivo depletion analysis with anti-CD4, anti-CD8 or anti-NK 1.1 McAb illustrated that both CD8+ T cells and CD4+ T cells played key roles in the augmented antitumor response of the combined therapy. Peptide/MHC tetramer represents a powerful and general tool for rapid, highly sensitive, and direct analysis of antigen-specific T cells. In this study, we prepared H-2Kb/TRP- 2180–188 tetramer, which was demonstrated to bind H-2Kb-restricted, B16 melanoma-specific CD8+T cells. B16 specific H-2Kb/TRP2180–188 tetramer was used to stain the tumor-specific CD8+ T cells and the results showed that CD8+ tetramer+ T cells were about 3–5% of the splenic CD8+ T cells derived from tumor-bearing mice after combined therapy. The CTL cytotoxicity was markedly induced in mice after combined therapy, suggesting efficient induction of tumor-specific CD8+ T cells after combined gene therapy with AdCD/5FC/AdIL18. IL-18 gene transfer could significantly augment the cytotoxicity of NK cells and macrophages, and increase the production of interleukin-2 and interferon-γ, as compared with treatments with AdCD/5FC, AdlacZ/5FC or PBS. These data suggested that in vivo IL-18 gene transfer could augment the antitumor effects of CD suicide gene therapy through efficient induction of antitumor immunity.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (39600181, 39708173) and National High Biotechnology Foundation of China (96Z032).

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Authors and Affiliations

  1. Department of Immunology, Second Military Medical University, Shanghai, P.R. China

    D W Ju, Q Tao, W G Song, L He, G Chen, S Gu & X Cao

  2. Laboratory of Immune cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Y Yang & C C Ting

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  1. D W Ju
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  2. Y Yang
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Ju, D., Yang, Y., Tao, Q. et al. Interleukin-18 gene transfer increases antitumor effects of suicide gene therapy through efficient induction of antitumor immunity. Gene Ther 7, 1672–1679 (2000). https://doi.org/10.1038/sj.gt.3301291

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