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Respective roles of TNF-α and IL-6 in the immune response-elicited by adenovirus-mediated gene transfer in mice

Gene Therapy volume 14, pages 533–544 (2007)Cite this article

A Corrigendum to this article was published on 06 March 2007

Abstract

The immunogenicity of recombinant adenoviruses (Ad) constitutes a major concern for their use in gene therapy. Antibody- and cell-mediated immune responses triggered by adenoviral vectors hamper long-term transgene expression and efficient viral readministration. We previously reported that interleukin (IL)-6 and tumor necrosis factor (TNF)-α play an essential role in both the acute phase and antibody response against Ad, respectively. As TNF-α controls the immune response and the development of the immune system, we examined here the consequence of blockade of TNF-α activity through Ad-mediated gene delivery of a dimeric mouse TNFR1-IgG fusion protein on transgene expression from a second Ad. Ad encoding TNFR1-IgG (AdTNFR1-Ig) was injected intravenously along with Ad encoding β-galactosidase or α1-antitrypsin transgene in wild-type (IL-6+/+) but also in IL-6-deficient mice (IL-6−/−) to analyze how TNF-α and IL-6 diminish liver gene transfer efficacy. Blockade of TNF-α leads to increased transgene expression in both wild-type and IL-6−/− mice due to a reduced inflammatory response and to diminished recruitment of macrophages and NK cells towards the liver. Antibody responses against adenoviral particles and expressed transgenes were only delayed in AdTNFR1-Ig-treated wild-type mice, but were markedly reduced in AdTNFR1-Ig-treated IL-6−/− mice. Finally, treatment of mice with etanercept, a clinically approved anti-TNF-α drug, confirmed the importance of controlling proinflammatory cytokines during gene therapy by adenoviral vectors.

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References

  1. Benihoud K, Yeh P, Perricaudet M . Adenovirus vectors for gene delivery. Curr Opin Biotechnol 1999; 10: 440–447.

    Article  CAS  PubMed  Google Scholar 

  2. Russell WC . Update on adenovirus and its vectors. J Gen Virol 2000; 81: 2573–2604.

    Article  CAS  PubMed  Google Scholar 

  3. Kochanek S, Schiedner G, Volpers C . High-capacity ‘gutless’ adenoviral vectors. Curr Opin Mol Ther 2001; 3: 454–463.

    CAS  PubMed  Google Scholar 

  4. McCoy RD, Davidson BL, Roessler BJ, Huffnagle GB, Janich SL, Laing TJ et al. Pulmonary inflammation induced by incomplete or inactivated adenoviral particles. Hum Gene Ther 1995; 6: 1553–1560.

    Article  CAS  PubMed  Google Scholar 

  5. Liu Q, Muruve DA . Molecular basis of the inflammatory response to adenovirus vectors. Gene Ther 2003; 10: 935–940.

    Article  CAS  PubMed  Google Scholar 

  6. Muruve DA, Barnes MJ, Stillman IE, Libermann TA . Adenoviral gene therapy leads to rapid induction of multiple chemokines and acute neutrophil-dependent hepatic injury in vivo. Hum Gene Ther 1999; 10: 965–976.

    Article  CAS  PubMed  Google Scholar 

  7. Borgland SL, Bowen GP, Wong NC, Libermann TA, Muruve DA . Adenovirus vector-induced expression of the C-X-C chemokine IP-10 is mediated through capsid-dependent activation of NF-kappaB. J Virol 2000; 74: 3941–3947.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tibbles LA, Spurrell JC, Bowen GP, Liu Q, Lam M, Zaiss AK et al. Activation of p38 and ERK signaling during adenovirus vector cell entry lead to expression of the C-X-C chemokine IP-10. J Virol 2002; 76: 1559–1568.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bowen GP, Borgland SL, Lam M, Libermann TA, Wong NC, Muruve DA . Adenovirus vector-induced inflammation: capsid-dependent induction of the C-C chemokine RANTES requires NF-kappa B. Hum Gene Ther 2002; 13: 367–379.

    Article  CAS  PubMed  Google Scholar 

  10. Kafri T, Morgan D, Krahl T, Sarvetnick N, Sherman L, Verma I . 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 

  11. Molinier-Frenkel V, Gahery-Segard H, Mehtali M, Le Boulaire C, Ribault S, Boulanger P et al. Immune response to recombinant adenovirus in humans: capsid components from viral input are targets for vector-specific cytotoxic T lymphocytes. J Virol 2000; 74: 7678–7682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. McCoy RD, Davidson BL, Roessler BJ, Huffnagle GB, Simon RH . Expression of human interleukin-1 receptor antagonist in mouse lungs using a recombinant adenovirus: effects on vector-induced inflammation. Gene Ther 1995; 2: 437–442.

    CAS  PubMed  Google Scholar 

  13. Shayakhmetov DM, Li ZY, Ni S, Lieber A . Interference with the IL-1-signaling pathway improves the toxicity profile of systemically applied adenovirus vectors. J Immunol 2005; 174: 7310–7319.

    Article  CAS  PubMed  Google Scholar 

  14. McElvaney NG, Crystal RG . IL-6 release and airway administration of human CFR cDNA adenovirus vector. Nat Med 1995; 1: 182–184.

    Article  CAS  PubMed  Google Scholar 

  15. Benihoud K, Salone B, Esselin S, Opolon P, Poli V, Di Giovine M et al. The role of IL-6 in the inflammatory and humoral response to adenoviral vectors. J Gene Med 2000; 2: 194–203.

    Article  CAS  PubMed  Google Scholar 

  16. Ginsberg HS, Moldawer LL, Sehgal PB, Redington M, Kilian PL, Chanock RM et al. A mouse model for investigating the molecular pathogenesis of adenovirus pneumonia. Proc Natl Acad Sci USA 1991; 88: 1651–1655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Otake K, Ennist DL, Harrod K, Trapnell BC . Nonspecific inflammation inhibits adenovirus-mediated pulmonary gene transfer and expression independent of specific acquired immune responses. Hum Gene Ther 1998; 9: 2207–2222.

    Article  CAS  PubMed  Google Scholar 

  18. Zhang Y, Chirmule N, Gao GP, Qian R, Croyle M, Joshi B et al. Acute cytokine response to systemic adenoviral vectors in mice is mediated by dendritic cells and macrophages. Mol Ther 2001; 3: 697–707.

    Article  CAS  PubMed  Google Scholar 

  19. Horwitz MS . Function of adenovirus E3 proteins and their interactions with immunoregulatory cell proteins. J Gene Med 2004; 6 (Suppl 1): S172–S183.

    Article  CAS  PubMed  Google Scholar 

  20. Lichtenstein DL, Toth K, Doronin K, Tollefson AE, Wold WS . Functions and mechanisms of action of the adenovirus E3 proteins. Int Rev Immunol 2004; 23: 75–111.

    Article  CAS  PubMed  Google Scholar 

  21. Fessler SP, Chin YR, Horwitz MS . Inhibition of tumor necrosis factor (TNF) signal transduction by the adenovirus group C RID complex involves downregulation of surface levels of TNF receptor 1. J Virol 2004; 78: 13113–13121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Benihoud K, Saggio I, Opolon P, Salone B, Amiot F, Connault E et al. Efficient, repeated adenovirus-mediated gene transfer in mice lacking both tumor necrosis factor alpha and lymphotoxin alpha. J Virol 1998; 72: 9514–9525.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Elkon KB, Liu CC, Gall JG, Trevejo J, Marino MW, Abrahamsen KA et al. Tumor necrosis factor alpha plays a central role in immune-mediated clearance of adenoviral vectors. Proc Natl Acad Sci USA 1997; 94: 9814–9819.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kolls J, Peppel K, Silva M, Beutler B . Prolonged and effective blockade of tumor necrosis factor activity through adenovirus-mediated gene transfer. Proc Natl Acad Sci USA 1994; 91: 215–219.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Poli V, Balena R, Fattori E, Markatos A, Yamamoto M, Tanaka H et al. Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion. EMBO J 1994; 13: 1189–1196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sung RS, Qin L, Bromberg JS . TNFalpha and IFNgamma induced by innate anti-adenoviral immune responses inhibit adenovirus-mediated transgene expression. Mol Ther 2001; 3: 757–767.

    Article  CAS  PubMed  Google Scholar 

  27. Varnavski AN, Calcedo R, Bove M, Gao G, Wilson JM . Evaluation of toxicity from high-dose systemic administration of recombinant adenovirus vector in vector-naive and pre-immunized mice. Gene Ther 2005; 12: 427–436.

    Article  CAS  PubMed  Google Scholar 

  28. Cichon G, Schmidt HH, Benhidjeb T, Loser P, Ziemer S, Haas R et al. Intravenous administration of recombinant adenoviruses causes thrombocytopenia, anemia and erythroblastosis in rabbits. J Gene Med 1999; 1: 360–371.

    Article  CAS  PubMed  Google Scholar 

  29. Muruve DA . The innate immune response to adenovirus vectors. Hum Gene Ther 2004; 15: 1157–1166.

    Article  CAS  PubMed  Google Scholar 

  30. Ben-Gary H, McKinney RL, Rosengart T, Lesser ML, Crystal RG . Systemic interleukin-6 responses following administration of adenovirus gene transfer vectors to humans by different routes. Mol Ther 2002; 6: 287–297.

    Article  PubMed  Google Scholar 

  31. Zhang HG, Zhou T, Yang P, Edwards III CK, Curiel DT, Mountz JD . Inhibition of tumor necrosis factor alpha decreases inflammation and prolongs adenovirus gene expression in lung and liver. Hum Gene Ther 1998; 9: 1875–1884.

    Article  CAS  PubMed  Google Scholar 

  32. Peng Y, Trevejo J, Zhou J, Marino MW, Crystal RG, Falck-Pedersen E et al. Inhibition of tumor necrosis factor alpha by an adenovirus-encoded soluble fusion protein extends transgene expression in the liver and lung. J Virol 1999; 73: 5098–5109.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Qin L, Ding Y, Pahud DR, Chang E, Imperiale MJ, Bromberg JS . Promoter attenuation in gene therapy: interferon-gamma and tumor necrosis factor-alpha inhibit transgene expression. Hum Gene Ther 1997; 8: 2019–2029.

    Article  CAS  PubMed  Google Scholar 

  34. Feldmann M, Maini RN . Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol 2001; 19: 163–196.

    Article  CAS  PubMed  Google Scholar 

  35. Starnes Jr HF, Pearce MK, Tewari A, Yim JH, Zou JC, Abrams JS . Anti-IL-6 monoclonal antibodies protect against lethal Escherichia coli infection and lethal tumor necrosis factor-alpha challenge in mice. J Immunol 1990; 145: 4185–4191.

    CAS  PubMed  Google Scholar 

  36. Rosen SD . Ligands for L-selectin: homing, inflammation, and beyond. Annu Rev Immunol 2004; 22: 129–156.

    Article  CAS  PubMed  Google Scholar 

  37. Trevejo JM, Marino MW, Philpott N, Josien R, Richards EC, Elkon KB et al. TNF-alpha-dependent maturation of local dendritic cells is critical for activating the adaptive immune response to virus infection. Proc Natl Acad Sci USA 2001; 98: 12162–12167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mitoma H, Horiuchi T, Hatta N, Tsukamoto H, Harashima S, Kikuchi Y et al. Infliximab induces potent anti-inflammatory responses by outside-to-inside signals through transmembrane TNF-alpha. Gastroenterology 2005; 128: 376–392.

    Article  CAS  PubMed  Google Scholar 

  39. Shen C, Maerten P, Geboes K, Van Assche G, Rutgeerts P, Ceuppens JL . Infliximab induces apoptosis of monocytes and T lymphocytes in a human-mouse chimeric model. Clin Immunol 2005; 115: 250–259.

    Article  CAS  PubMed  Google Scholar 

  40. Kirchner S, Holler E, Haffner S, Andreesen R, Eissner G . Effect of different tumor necrosis factor (TNF) reactive agents on reverse signaling of membrane integrated TNF in monocytes. Cytokine 2004; 28: 67–74.

    Article  CAS  PubMed  Google Scholar 

  41. Aversa G, Punnonen J, de Vries JE . The 26-kD transmembrane form of tumor necrosis factor alpha on activated CD4+ T cell clones provides a costimulatory signal for human B cell activation. J Exp Med 1993; 177: 1575–1585.

    Article  CAS  PubMed  Google Scholar 

  42. Fujii T, Okada M, Mimori T, Craft J . The transmembrane form of TNF-alpha drives autoantibody production in the absence of CD154: studies using MRL/Mp-Fas(lpr) mice. Clin Exp Immunol 2002; 130: 224–232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Philpott NJ, Nociari M, Elkon KB, Falck-Pedersen E . Adenovirus-induced maturation of dendritic cells through a PI3 kinase-mediated TNF-alpha induction pathway. Proc Natl Acad Sci USA 2004; 101: 6200–6205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Krasnykh VN, Douglas JT, van Beusechem VW . Genetic targeting of adenoviral vectors. Mol Ther 2000; 1: 391–405.

    Article  CAS  PubMed  Google Scholar 

  45. Mizuguchi H, Hayakawa T . Targeted adenovirus vectors. Hum Gene Ther 2004; 15: 1034–1044.

    Article  CAS  PubMed  Google Scholar 

  46. Tran PL, Weinbach J, Opolon P, Linares-Cruz G, Reynes JP, Gregoire A et al. Prevention of bleomycin-induced pulmonary fibrosis after adenovirus-mediated transfer of the bacterial bleomycin resistance gene. J Clin Invest 1997; 99: 608–617.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gilardi P, Courtney M, Pavirani A, Perricaudet M . Expression of human alpha 1-antitrypsin using a recombinant adenovirus vector. FEBS Lett 1990; 267: 60–62.

    Article  CAS  PubMed  Google Scholar 

  48. Griscelli F, Li H, Bennaceur-Griscelli A, Soria J, Opolon P, Soria C et al. Angiostatin gene transfer: inhibition of tumor growth in vivo by blockage of endothelial cell proliferation associated with a mitosis arrest. Proc Natl Acad Sci USA 1998; 95: 6367–6372.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Fallaux FJ, Kranenburg O, Cramer SJ, Houweling A, Van Ormondt H, Hoeben RC et al. Characterization of 911: a new helper cell line for the titration and propagation of early region 1-deleted adenoviral vectors. Hum Gene Ther 1996; 7: 215–222.

    Article  CAS  PubMed  Google Scholar 

  50. Michalski JP, McCombs CC, Sheth S, McCarthy M, deShazo R . A modified double antibody sandwich enzyme-linked immunosorbent assay for measurement of alpha-1-antitrypsin in biologic fluids. J Immunol Methods 1985; 83: 101–112.

    Article  CAS  PubMed  Google Scholar 

  51. Ohmori Y, Wyner L, Narumi S, Armstrong D, Stoler M, Hamilton TA . Tumor necrosis factor-alpha induces cell type and tissue-specific expression of chemoattractant cytokines in vivo. Am J Pathol 1993; 142: 861–870.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Saulnier P, Vidaud M, Gautier E, Motte N, Bellet D, Escudier B et al. Development and validation of a real-time PCR assay for the detection and quantitation of p53 recombinant adenovirus in clinical samples from patients treated with Ad5CMV-p53 (INGN 201). J Virol Methods 2003; 114: 55–64.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Bruce Beutler (Department of Immunology, The Scripps Research Institute, La Jolla, CA) and Valeria Poli (Department of Genetics, Biology and Biochemistry, University of Turin, Italy) for providing AdTNFR1-Ig and IL-6 knockout mice, respectively. We are profoundly indebted to Patrick Saulnier and Laure Franqueville for real-time PCR analysis and viral stock preparations, respectively. We wish to thank all the staff of the animal facilities and particularly Monique Stanciu for her excellent technical assistance. We thank Brian Mullan for proofreading of the manuscript.

This work was supported by the Centre National de la Recherche Scientifique (CNRS), Vaincre la Mucoviscidose, and the Association Française pour la Myopathie (AFM). KB was supported by Vaincre la Mucoviscidose. DD and BJ received fellowships from the Ministère de la Recherche et de la Technologie and DD received another fellowship from Vaincre la Mucoviscidose.

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Authors and Affiliations

  1. Univ Paris-Sud, Faculté des Sciences, Orsay, Cedex, France

    K Benihoud, S Esselin, D Descamps, B Jullienne, E Connault, P Opolon & M Perricaudet

  2. CNRS UMR 8121, Institut Gustave Roussy, Villejuif, Cedex, France

    K Benihoud & P Bobé

  3. Department of Genetics and Molecular Biology, University of Rome La Sapienza, Rome, Italy

    B Salone & I Saggio

  4. CNRS UPR 9045, Villejuif, Cedex, France

    P Bobé & D Bonardelle

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  1. K Benihoud
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Correspondence to K Benihoud.

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This article is dedicated to the memory of our colleague and friend S Esselin (6 November 1974 to 28 May 2006).

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Benihoud, K., Esselin, S., Descamps, D. et al. Respective roles of TNF-α and IL-6 in the immune response-elicited by adenovirus-mediated gene transfer in mice. Gene Ther 14, 533–544 (2007). https://doi.org/10.1038/sj.gt.3302885

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