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Effect of tolerance induction to immunodominant T-cell epitopes of Sendai virus on gene expression following repeat administration to lung

Gene Therapy volume 13, pages 449–456 (2006)Cite this article

Abstract

Sendai virus (SeV) is able to transfect airway epithelial cells efficiently in vivo. However, as with other viral vectors, repeated administration leads to reduced gene expression. We have investigated the impact of inducing immunological tolerance to immunodominant T-cell epitopes on gene expression following repeated administration. Immunodominant CD4 and CD8 T-cell peptide epitopes of SeV were administered to C57BL/6 mice intranasally 10 days before the first virus administration with transmission-incompetent F-protein-deleted ΔF/SeV-GFP. At 21 days after the first virus administration, mice were again transfected with ΔF/SeV. To avoid interference of anti-GFP antibodies, the second transfection was carried out with ΔF/SeV-lacZ. At 2 days after the final transfection lung β-galactosidase expression, T-cell proliferation and antibody responses were measured. A state of ‘split tolerance’ was achieved with reduced T-cell proliferation, but no impact on antiviral antibody production. There was no enhancement of expression on repeat administration; instead, T-cell tolerance was, paradoxically, associated with a more profound extinction of viral expression. Multiple immune mechanisms operate to eradicate viruses from the lung, and these findings indicate that impeding the adaptive T-cell response to the immunodominant viral epitope is not sufficient to prevent the process.

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Acknowledgements

This work was supported by a Cystic Fibrosis Trust Senior Research Fellowship (UG) and a Medical Research Council Clinician Scientist Fellowship (RJB) and the Cystic Fibrosis Trust.

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Author notes

  1. U Griesenbach and R J Boyton: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Gene Therapy, NHLI, Imperial College, Edinburgh, London, UK

    U Griesenbach, L Somerton, S E Garcia, S Ferrari, T Owaki, D M Geddes & E W F W Alton

  2. UK Cystic Fibrosis Gene Therapy Consortium, London, UK

    U Griesenbach, L Somerton, S E Garcia, S Ferrari, D M Geddes & E W F W Alton

  3. Department of Biological Sciences/NHLI, Lung Immunology Group, Imperial College, London, UK

    R J Boyton

  4. DNAVEC Research Inc., Tsukuba, Ibaraki, Japan

    T Owaki, Z Ya-Fen & M Hasegawa

  5. Department of Infectious Diseases, Human Disease Immunogenetics Group, Imperial College, London, UK

    D M Altmann

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  1. U Griesenbach
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Griesenbach, U., Boyton, R., Somerton, L. et al. Effect of tolerance induction to immunodominant T-cell epitopes of Sendai virus on gene expression following repeat administration to lung. Gene Ther 13, 449–456 (2006). https://doi.org/10.1038/sj.gt.3302677

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