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Immunostimulatory DNA-based vaccines induce cytotoxic lymphocyte activity by a T-helper cell-independent mechanism

Nature Biotechnology volume 18, pages 509–514 (2000)Cite this article

Abstract

Immunostimulatory DNA sequences (ISS) contain unmethylated CpG dinucleotides within a defined motif. Immunization with ISS-based vaccines has been shown to induce high antigen-specific cytotoxic lymphocyte (CTL) activity and a Th1-biased immune response. We have developed a novel ISS-based vaccine composed of ovalbumin (OVA) chemically conjugated to ISS–oligodeoxynucleotide (ODN). Protein–ISS conjugate (PIC) is more potent in priming CTL activity and Th1-biased immunity than other ISS-based vaccines. Cytotoxic lymphocyte activation by ISS–ODN-based vaccines is preserved in both CD4−/− and MHC class II−/− gene-deficient animals. Furthermore, PIC provides protection against a lethal burden of OVA-expressing tumor cells in a CD8+ cell-dependent manner. These results demonstrate that PIC acts through two unique mechanisms: T-helper-independent activation of CTL and facilitation of exogenous antigen presentation on MHC class I. This technology may have clinical applications in cancer therapy and in stimulating host defense in AIDS and chronic immunosuppression.

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Figure 1: Synthesis of ovalbumin–ISS–ODN conjugate.
Figure 2: Antigen-specific cytotoxic lymphocyte activity following intradermal immunization of test animals on days zero and 14 with the following vaccines: PIC (50 μg, ▪), OVA + ISS–ODN coadministration (50 μg each, ♦), mPIC (50 μg, ⋄), pACB–OVA (50 μg, ●, or OVA alone (50 μg, ▴).
Figure 3: PIC vaccination induces a Th1-biased immune response.
Figure 4: Activation of CTL activity by PIC is independent of MHC class II-restricted help.
Figure 5: Plot showing that PIC vaccination provides protective immunity in both preventive and therapeutic models of cancer.
Figure 6: ISS-based vaccines provide T-helper-independent “licensing” of APC and facilitation of exogenous antigen presentation on MHC class I.

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Acknowledgements

The authors wish to thank Tomoko Hayashi, Yucan Chiu, and Nadya Cinman for expert technical assistance, and Nancy Noon and Jane Uhle for editorial assistance. We also thank Wei Ping Feung-Leung and Tak Mak for the generous gift of CD8−/− mice, and Angel Porgador and Eli Gilboa for the generous gift of the E.G7–OVA cell line. This work was supported in part by grants from the National Institutes of Health (AI 40682, AI 47078, and AR 44850) and by Dynavax Technologies. H.J.C. is supported by a research resident fellowship from the Sam and Rose Stein Institute for Research on Aging (La Jolla, CA).

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  1. Department of Internal Medicine and The Sam and Rose Stein Institute for Research on Aging, University of California San Diego, La Jolla, CA 92093-0663

    Hearn Jay Cho, Kenji Takabayashi, Pei-Ming Cheng, Minh-Duc Nguyen, Maripat Corr & Eyal Raz

  2. Dynavax Technologies Corp., 717 Potter Street, Berkeley, CA 94710

    Stephen Tuck

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Correspondence to Eyal Raz.

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Cho, H., Takabayashi, K., Cheng, PM. et al. Immunostimulatory DNA-based vaccines induce cytotoxic lymphocyte activity by a T-helper cell-independent mechanism. Nat Biotechnol 18, 509–514 (2000). https://doi.org/10.1038/75365

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