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Plant viral genes in DNA idiotypic vaccines activate linked CD4+ T-cell mediated immunity against B-cell malignancies

Nature Biotechnology volume 19, pages 760–764 (2001)Cite this article

Abstract

DNA delivery of tumor antigens can activate specific immune attack on cancer cells. However, antigens may be weak and immune capacity can be compromised. Fusion of genes encoding activating sequences to the tumor antigen sequence facilitates promotion and manipulation of effector pathways. Idiotypic determinants of B-cell tumors, encoded by the variable region genes, are clone-specific tumor antigens. When assembled as single-chain Fv (scFv) alone in a DNA vaccine, immunogenicity is low. Previously, we found that fusion of a sequence from tetanus toxin (fragment C; FrC) promoted anti-idiotypic protection against lymphoma and myeloma. We have now investigated an alternative fusion gene derived from a plant virus, potato virus X coat protein, a primary antigen in humans. When fused to scFv, the self-aggregating protein generates protection against lymphoma and myeloma. In contrast to scFv–FrC, protection against lymphoma is mediated by CD4+ T cells, as is protection against myeloma. Plant viral proteins offer new opportunities to activate immunity against linked T-cell epitopes to attack cancer.

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References

  • Syrengelas, A.D., Chen, T.T. & Levy, R. DNA immunization induces protective immunity against B-cell lymphoma. Nat. Med. 2, 1038–1041 (1996).

    Article  CAS  Google Scholar 

  • Biragyn, A., Tani, K., Grimm, M.C., Weeks, S. & Kwak, L.W. Genetic fusion of chemokines to a self tumor antigen induces protective, T-cell dependent antitumor immunity. Nat. Biotechnol. 17, 253–258 (1999).

    Article  CAS  Google Scholar 

  • Conry, R.M. et al. Selected strategies to augment polynucleotide immunization. Gene Ther. 3, 67–74 (1996).

    CAS  PubMed  Google Scholar 

  • Hawkins, R.E. et al. Idiotypic vaccination against human B-cell lymphoma. Rescue of variable region gene sequences from biopsy material for assembly as single-chain Fv personal vaccines. Blood 83, 3279–3288 (1994).

    Article  CAS  Google Scholar 

  • Spellerberg, M.B. et al. DNA vaccines against lymphoma. Promotion of anti-idiotypic antibody responses induced by single chain Fv genes by fusion to tetanus toxin fragment C. J. Immunol. 159, 1885–1892 (1997).

    CAS  PubMed  Google Scholar 

  • King, C.A. et al. DNA vaccines with single chain Fv fused to fragment C of tetanus toxin induce protective immunity against lymphoma and myeloma. Nat. Med. 4, 1281–1286 (1998).

    Article  CAS  Google Scholar 

  • Dembic, Z., Schenck, K. & Bogen, B. Dendritic cells purified from myeloma are primed with tumour-specific antigen (idiotype) and activate CD4+ T cells. Proc. Natl. Acad. Sci. USA 97, 2697–2702 (2000).

    Article  CAS  Google Scholar 

  • Qin, Z. & Blankenstein, T. CD4+ T cell-mediated tumor rejection involves inhibition of angiogenesis that is dependent on IFN-γ receptor expression by nonhematopoietic cells. Immunity 12, 677–686 (2000).

    Article  CAS  Google Scholar 

  • Mumberg, D. et al. CD4+ T cells eliminate MHC class II-negative cancer cells in vivo by indirect effect of IFN-γ. Proc. Natl. Acad. Sci. USA 96, 8633–8638 (1999).

    Article  CAS  Google Scholar 

  • Haynes, J.R. et al. Development of a genetically-engineered, candidate polio vaccine employing the self-assembling properties of the tobacco mosaic virus coat protein. Biotechnology 4, 637–641 (1986).

    CAS  PubMed  Google Scholar 

  • Turpen, T.H. et al. Malarial epitopes expressed on the surface of recombinant tobacco mosaic virus. Biotechnology 13, 53–57 (1995).

    CAS  PubMed  Google Scholar 

  • Dalsgaard, K. et al. Plant-derived vaccine protects target animals against a viral disease. Nat. Biotechnol. 15, 248–252 (1997).

    Article  CAS  Google Scholar 

  • Lomonossoff, G.P. & Johnson, J.E. Use of macromolecular assemblies as expression systems for peptides and synthetic vaccines. Curr. Opin. Struct. Biol. 6, 176–182 (1996).

    Article  CAS  Google Scholar 

  • Santa Cruz, S. et al. Assembly and movement of a plant virus carrying a green fluorescent protein overcoat. Proc. Natl. Acad. Sci. USA 93, 6286–6290 (1996).

    Article  CAS  Google Scholar 

  • Brennan, F.R. et al. Immunogenicity of peptides derived from a fibronectin-binding protein of S. aureus expressed on two different plant viruses. Vaccine 17, 1846–1857 (1999).

    Article  CAS  Google Scholar 

  • Smolenska, L. et al. Production of a functional single chain antibody attached to the surface of a plant virus. FEBS Lett. 441, 379–382 (1998).

    Article  CAS  Google Scholar 

  • Hinrichs, J., Berger, S. & Shaw, J.G. Induction of antibodies to plant viral proteins by DNA-based immunization. J. Virol. Methods 66, 195–202 (1997).

    Article  CAS  Google Scholar 

  • Goodman, R.M., Horne, R.W. & Hobart, J.M. Reconstitution of potato virus X in vitro. Virology 68, 299–308 (1975).

    Article  CAS  Google Scholar 

  • Erickson, J.W., Bancroft, J.B. & Stillman, M.J. Circular dichroism studies of papaya mosaic virus coat protein and its polymers. J. Mol. Biol. 147, 337–349 (1981).

    Article  CAS  Google Scholar 

  • Gurunathan, S., Klinman, D.M. & Seder, R.A. DNA vaccines: immunology, application and optimization. Annu. Rev. Immunol. 18, 927–974 (2000).

    Article  CAS  Google Scholar 

  • Stevenson, F.K. et al. Idiotypic DNA vaccines against B-cell lymphoma. Immunol. Rev. 145, 211–228 (1995).

    Article  CAS  Google Scholar 

  • Gerloni, M. et al. Functional cooperation between T helper cell determinants. Proc. Natl. Acad. Sci. USA 97, 13269–13274 (2000).

    Article  CAS  Google Scholar 

  • Zinkernagel, R.M. Immunology and autoimmunity studied with viruses. in The molecular basis of cellular defence mechanisms. (Ciba Foundation Symposium 204). 105–129 (Wiley, Chichester, UK; 1997).

  • Ulmer, J.B., Deck, R.R., Dewitt, C.M., Donnelly, J.J. & Liu, M.A. Generation of MHC class I-restricted cytotoxic T lymphocytes by expression of a viral protein in muscle cells: antigen presentation by non-muscle cells. Immunology 89, 59–67 (1996).

    Article  CAS  Google Scholar 

  • Corr, M., von Damm, A., Lee, D.L. & Tighe, H. In vivo priming by DNA occurs predominantly by antigene transfer. J. Immunol. 163, 4721–4727 (1999).

    CAS  PubMed  Google Scholar 

  • Condon, C., Watkins, S.C., Celluzzi, C.M., Thompson, K. & Falo, L.D. Jr. DNA-based immunization by in vivo transfection of dendritic cells. Nat. Med. 2, 1122–1128 (1996).

    Article  CAS  Google Scholar 

  • Casares, S., Inaba, K., Brumeanu, T.D., Steinman, R.M. & Bona, C.A. Antigen presentation by dendritic cells after immunization with DNA encoding a major histocompatibility complex class II-restricted viral epitope. J. Exp. Med. 186, 1481–1486 (1997).

    Article  CAS  Google Scholar 

  • Roman, M. et al. Immunostimulatory DNA sequences function as T helper-1-promoting adjuvants. Nat. Med. 3, 849–854 (1997).

    Article  CAS  Google Scholar 

  • McInerney, T.L., Brennan, F.R., Jones, T.D. & Dimmock, N.J. Analysis of the ability of five adjuvants to enhance immune responses to a chimeric plant virus displaying an HIV-1 peptide. Vaccine 17, 1359–1368 (1999).

    Article  CAS  Google Scholar 

  • Stevenson, F.K. et al. Genetic vaccination against defined tumour antigens of B-cell malignances. Rev. Clin. Exp. Hematol. 9, 2–21 (1999).

    Google Scholar 

  • Zhu, D. et al. Immunoglobulin VH gene sequence analysis of spontaneous murine immunoglobulin-secreting B-cell tumours with clinical features of human disease. Immunology 93, 162–170 (1998).

    Article  CAS  Google Scholar 

  • Cobbold, S.P., Jayasuriya, A., Nash, A., Prospero, T.D., Waldmann, H. Therapy with monoclonal antibodies by elimination of T-cell subsets in vivo. Nature 312, 548–551 (1984).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the Leukaemia Research Fund UK and Tenovus, UK. We thank Mike Shanks for assistance with the electron microscopy. We also thank Kerry Cox for excellent technical assistance.

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Authors and Affiliations

  1. Molecular Immunology Group, Tenovus Laboratory, Southampton University Hospitals Trust, Southampton, SO16 6YD, United Kingdom

    Natalia Savelyeva, Rosalind Munday, Myfanwy B. Spellerberg & Freda K. Stevenson

  2. Department of Virus Research, John Innes Centre, Colney Lane, Norwich, NR4 7UH, United Kingdom

    George P. Lomonossoff

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  1. Natalia Savelyeva
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  2. Rosalind Munday
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  3. Myfanwy B. Spellerberg
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  4. George P. Lomonossoff
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  5. Freda K. Stevenson
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Savelyeva, N., Munday, R., Spellerberg, M. et al. Plant viral genes in DNA idiotypic vaccines activate linked CD4+ T-cell mediated immunity against B-cell malignancies. Nat Biotechnol 19, 760–764 (2001). https://doi.org/10.1038/90816

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