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T-cell response to adenovirus hexon and DNA-binding protein in mice

Gene Therapy volume 11, pages 791–796 (2004)Cite this article

Abstract

The successful development of adenovirus vectors for vaccines and gene therapy will require a better understanding of the host immune response. Using the ELISPOT assay to measure IFN-γ-secreting CD8+ cells, we identify immunodominant epitopes of the adenovirus hexon and DNA-binding protein in BALB/c and C57BL/6 mice. The T-cell response to the intramuscular administration of adenovirus serotype 5 peaks within a few weeks and gradually declines but is still detectable after 12 weeks. A second administration did not substantially increase the number of reactive T cells. The CD8+ T-cell response was also similar between wild type and E1-deleted adenovirus. When B-cell-deficient mice were injected with adenovirus encoding the gene for secreted alkaline phosphatase, sera phosphatase activity was reduced more quickly in mice pre-exposed to adenovirus. These results add to the evidence that cell-mediated immunity is a substantial barrier to therapeutic adenoviral vectors and provide more quantitative tools to measure cellular immune responses to adenovirus.

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References

  1. Yang Y, Li Q, Ertl HCJ, Wilson JM . Cellular and humoral immune responses to viral antigens create barriers to lung-directed gene therapy with recombinant adenoviruses. J Virol 1995; 69: 2004–2015.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Yei S et al. Adenovirus-mediated gene transfer for cystic fibrosis: quantitative evaluation of repeated in vivo vector administration to the lung. Gene Therapy 1994; 1: 192–200.

    CAS  PubMed  Google Scholar 

  3. Dai Y et al. Cellular and humoral immune responses to adenoviral vectors containing factor IX gene: tolerization of factor IX and vector antigens allows for long-term expression. Proc Natl Acad Sci USA 1995; 92: 1401–1405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. DeMatteo RP et al. Immunological barriers to hepatic adenoviral gene therapy for transplantation. Transplantation 1997; 63: 315–319.

    Article  CAS  PubMed  Google Scholar 

  5. Yang Y, Haecker S, Su Q, Wilson JM . Immunology of gene therapy with adenoviral vectors in mouse skeletal muscle. Hum Mol Gen 1996; 5: 1703–1712.

    Article  CAS  PubMed  Google Scholar 

  6. Tripathy SK, Black HB, Goldwasser E, Leiden JM . Immune responses to transgene-encoded proteins limit the stability of gene expression after injection of replication-defective adenovirus vectors. Nat Med 1996; 2: 545–550.

    Article  CAS  PubMed  Google Scholar 

  7. Gahery-Segard H et al. Immune response to recombinant capsid proteins of adenovirus in humans: antifiber and anti-penton base antibodies have a synergistic effect on neutralizing activity. J Virol 1998; 72: 2388–2397.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Chen P, Kovesdi I, Bruder JT . Effective repeat administration with adenovirus vectors to the muscle. Gene Therapy 2000; 7: 587–595.

    Article  CAS  PubMed  Google Scholar 

  9. Yang Y, Ertl HCJ, Wilson JM . MHC class I-restricted cytotoxic T-lymphocytes to viral antigens destroy hepatocytes in mice infected with E1-deleted recombinant adenoviruses. Immunity 1994; 1: 433–442.

    Article  CAS  PubMed  Google Scholar 

  10. Yang Y, Su Q, Wilson JM . Role of viral antigens in destructive cellular immune responses to adenovirus vector-transduced cells in mouse lungs. J Virol 1996; 70: 7209–7212.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Yang Y et al. Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. Proc Natl Acad Sci USA 1994; 91: 4407–4411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kafri T et al. Cellular immune response to adenoviral vector infected cells does not require de novo viral gene expression: implications for gene therapy. Proc Natl Acad Sci USA 1998; 95: 11377–11382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jooss K, Ertl HCJ, Wilson J . Cytotoxic T-lymphocyte target proteins and their major histocampatibilty complex class I restriction in response to adenovirus vectors delivered to mouse liver. J Virol 1998; 72: 2945–2954.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Molinier-Frenkel V et al. Adenovirus hexon protein is a potent adjuvant for activation of a cellular immune response. J Virol 2002; 76: 127–135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Olive M et al. The adenovirus capsid protein hexon contains a highly conserved human CD4+ T-cell epitope. Hum Gene Ther 2002; 13: 1167–1178.

    Article  CAS  PubMed  Google Scholar 

  16. Molinier-Frenkel V et al Immune response to recombinant adenovirus in humans: capsid proteins from viral input are targets for vector-specific cytotoxic T lymphocytes. J Virol 2000; 74 (16): 7678–7682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chirmule N et al. Role of E4 in eliciting CD4 T-cell and B-cell responses to adenovirus vectors delivered to murine and nonhuman primate lungs. J Virol 1998; 72: 6138–6145.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Lusky M et al. In vitro and in vivo biology of recombinant adenovirus vectors with E1, E1/E2A, or E1/E4 deleted. J Virol 1998; 72: 2022–2032.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Morsy M et al An adenoviral vector deleted for all viral coding sequences results in enhanced safety and extended expression of a leptin transgene. Appl Biol Sci 1998; 95: 7866–7871.

    CAS  Google Scholar 

  20. Ilan Y et al. Insertion of the adenoviral E3 region into a recombinant viral vector prevents antiviral humoral and cellular immune responses and permits long-term gene expression. Proc Natl Acad Sci USA 1997; 94: 2587–2592.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mastrangeli A et al. Sero-switch adenovirus-mediated in vivo gene transfer: circumvention of anti-adenovirus humoral immune defenses against repeat adenovirus vector administration by changing the adenovirus serotype. Hum Gene Ther 1996; 7: 79–87.

    Article  CAS  PubMed  Google Scholar 

  22. Mack CA et al. Circumvention of anti-adenovirus neutralizing immunity by administration of an adenoviral vector of an alternate serotype. Hum Gene Ther 1997; 8: 99–109.

    Article  CAS  PubMed  Google Scholar 

  23. Qin L et al. Adenovirus-mediated gene transfer of viral interleukin-10 inhibits the immune response to both alloantigen and adenoviral antigen. Hum Gene Ther 1997; 8: 1365–1374.

    Article  CAS  PubMed  Google Scholar 

  24. Peng Y, Falck-Pedersen E, Elkon KB . Soluble CD8 attenuates cytotoxic T-cell responses against replication-defective adenovirus affording transprotection of transgene in vivo. J Immun 2000; 165: 1470–1478.

    Article  CAS  PubMed  Google Scholar 

  25. Jooss K, Yang Y, Wilson J . Cyclophosphamide diminishes inflammation and prolongs transgene expression following delivery of adenoviral vectors to mouse liver and lung. Hum Gene Ther 1996; 7: 1555–1566.

    Article  CAS  PubMed  Google Scholar 

  26. Fallaux FJ et al New helper cells and matched early region 1-deleted adenovirus vectors prevent generation of replication-competent adenoviruses. Hum Gene Ther 1998; 9: 1909–1917.

    Article  CAS  PubMed  Google Scholar 

  27. Berger J et al. Secreted placental alkaline phosphatase: a powerful new quantitative indicator of gene expression in eukaryotic cells. Gene 1988; 66: 1–10.

    Article  CAS  PubMed  Google Scholar 

  28. Chapman B, Thayer R, Vincent K, Haigwood N . Effect of intron A from human cytomegalovirus (Towne) immediate-early gene on heterologous expression in mammalian cells. Nucleic Acids Res 1991; 19: 3979–3986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Klinman DM, Nutman TB . ELISPOT Assay to detect cytokine-secreting murine and human cells. In: Coligan JE et al (ed). Current Protocols in Immunology. John Wiley & Sons, Inc: New York, 1994; 1:pp 6.19.1–8.

    Google Scholar 

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  1. Department of Viral Vaccine Research, Merck Research Laboratories, West Point, PA, USA

    T McKelvey, A Tang, A J Bett, D R Casimiro & M Chastain

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  1. T McKelvey
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McKelvey, T., Tang, A., Bett, A. et al. T-cell response to adenovirus hexon and DNA-binding protein in mice. Gene Ther 11, 791–796 (2004). https://doi.org/10.1038/sj.gt.3302232

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