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  • Viral Transfer Technology
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Intra-CSF administered recombinant adenovirus causes an immune response-mediated toxicity

Gene Therapy volume 7, pages 1401–1409 (2000)Cite this article

Abstract

High doses of adenotk were injected into the cerebrospinal fluid of rats and nonhuman primates (Macaca mulatta). Vector administration was followed by ganciclovir administration for 14 days. Despite the absence of clinical symptoms, analysis of the cerebrospinal fluid (CSF) and histopathological examination of the central nervous system (CNS) of the monkeys (3 weeks after vector injection) were consistent with a viral meningitis. Immunohistochemical analysis of the inflammatory infiltrates in the monkeys revealed the presence of T and B lymphocytes, indicating a combined cellular and humoral immune response to the vector. This latter was supported by the finding of intrathecal anti-adenovirus antibody synthesis. Rats receiving high intrathecal adenotk doses showed a transient and dose-dependent clinical toxicity consisting of lethargy, hyperemic eyes and weight loss. Histopathological examination of the meninges showed a shift from polymorphonuclear infiltrates during the first post-injection days to clusters of mononuclear cells after 7 days. Acute toxicity is probably related to the early, innate immune response to the vector. In a separate experiment, high levels of IL-8 and IL-6, were measured during the first 2–3 post-injection days in the CSF of two monkeys which received intrathecal adenoLacZ. Therefore, these cytokines seem to play an important role in initiating the nonspecific immune response. In one monkey which received adenotk, recombinant adenovirus was cultured from serum samples obtained at the 7th post-injection day. At this time-point, no vector could be isolated from CSF samples. Based on these preclinical data, we recommend careful dose finding for clinical studies that aim to treat patients with leptomeningeal metastases.

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References

  1. Posner JB . Leptomeningeal metastases. In: Neurologic Complications of Cancer FA Davis: Philadelphia 1995 pp 143–171

  2. Vrionis FD et al. Tumor cells expressing the herpes simplex virus-thymidine kinase gene in the treatment of Walker 256 meningeal neoplasia in rats J Neurosurg 1996 84: 250–257

    Article  CAS  PubMed  Google Scholar 

  3. Ram Z et al. Intrathecal gene therapy for malignant leptomeningeal neoplasia Cancer Res 1994 54: 2141–2145

    CAS  PubMed  Google Scholar 

  4. Kramm CM et al. Long-term survival in a rodent model of disseminated brain tumors by combined intrathecal delivery of herpes vectors and ganciclovir treatment Hum Gene Ther 1996 7: 1989–1994

    Article  CAS  PubMed  Google Scholar 

  5. Vincent AJPE et al. Treatment of leptomeningeal metastases in a rat model using a recombinant adenovirus containing the HSV-tk gene J Neurosurg 1996 85: 648–654

    Article  CAS  PubMed  Google Scholar 

  6. Oshiro EM et al. Toxicity studies and distribution dynamics of retroviral vectors following intrathecal administration of retroviral vector-producer cells Cancer Gene Ther 1995 2: 87–95

    CAS  PubMed  Google Scholar 

  7. Morral N et al. Immune responses to reporter proteins and high viral dose limit duration of expression with adenoviral vectors: comparison of E2a wild type and E2a deleted vectors Hum Gene Ther 1997 8: 1275–1286

    Article  CAS  PubMed  Google Scholar 

  8. Driesse MJ et al. Distribution of recombinant adenovirus in the cerebrospinal fluid of nonhuman primates Hum Gene Ther 1999 10: 2347–2354

    Article  CAS  PubMed  Google Scholar 

  9. Ginsberg HS 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 

  10. Cartmell T et al. Interkeukin-1 mediates a rapid inflammatory response after injection of adenoviral vectors into the brain J Neurosci 1999 19: 1517–1523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Amin A et al. Replication-deficient adenovirus induced expression of interleukin-8 by airway epithelial cells in vitro Hum Gene Ther 1995 6: 145–153

    Article  CAS  PubMed  Google Scholar 

  12. Bruder JT, Kovesdi I . Adenovirus infection stimulates the Raf/MAPK signaling pathways and induces interleukin-8 expression J Virol 1997 71: 398–404

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Richter CB, Lehner NDM, Henrickson RV . Primates In: Fox JG, Cohen BJ, Loew FM (eds) Laboratory Animal Medicine Academic Press: New York 1984 p306

    Google Scholar 

  14. Kennedy CR et al. A major role for viruses in acute childhood encephalopathy Lancet 1986 1: 989–991

    Article  CAS  PubMed  Google Scholar 

  15. Adesanya MR, Redman RS, Baum BJ, O'Connell BC . Immediate inflammatory responses to adenovirus-mediated gene transfer in rat salivary glands Hum Gene Ther 1996 7: 1085–1093

    Article  CAS  PubMed  Google Scholar 

  16. Worgall S, Wolff G, Falck-Pedersen E, Crystal RG . Innate immune mechanisms dominate elimination of adenoviral vectors following in vivo administration Hum Gene Ther 1997 8: 37–44

    Article  CAS  PubMed  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. Byrnes AP, Rusby JE, Wood MJA, Charlton HM . Adenovirus gene transfer causes inflammation in the brain Neuroscience 1995 66: 1015–1024

    Article  CAS  PubMed  Google Scholar 

  19. Hermens WTJMC, Verhaagen J . Adenoviral vector-mediated gene transfer in immuno competent Wister rats and T-cell deficient nude rats: preferential survival of transduced glial cells in nude rats Hum Gene Ther 1997 8: 1049–1063

    Article  CAS  PubMed  Google Scholar 

  20. Crystal RG et al. Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis Nat Genet 1994 8: 42–51

    Article  CAS  PubMed  Google Scholar 

  21. 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 

  22. Yang Y, Li Q, Ertl HC, 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 

  23. 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 Nature Med 1996 2: 545–550

    Article  CAS  PubMed  Google Scholar 

  24. Russi TJ, Hirschowitz EA, Crystal RG . Delayed-type hypersensitivity response to high dose of adenoviral vectors Hum Gene Ther 1997 8: 323–330

    Article  CAS  PubMed  Google Scholar 

  25. Song W, Kong H-L, Traktman P, Crystal RG . Cytotoxic T lymphocyte responses to proteins encoded by heterologous transgenes transferred in vivo by adenoviral vectors Hum Gene Ther 1997 8: 1207–1217

    Article  CAS  PubMed  Google Scholar 

  26. Byrnes AP, MacLaren RE, Charlton HM . Immunological instability of persistent adenovirus vectors in the brain: peripheral exposure to vector leads to renewed inflammation, reduced gene expression, and demyelination J Neurosci 1996 16: 3045–3055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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 

  28. Gordon LB, Knopf PM, Cserr HF . Ovalbumin is more immunogenic when introduced into brain or cerebrospinal fluid than into extracerebral sites J Neuroimmunol 1992 40: 81–88

    Article  CAS  PubMed  Google Scholar 

  29. Cserr HF et al. Afferent and efferent arms of the humoral immune response to CSF-administered albumins in a rat model with normal blood–brain barrier permeability J Neuroimmunol 1992 41: 195–202

    Article  CAS  PubMed  Google Scholar 

  30. Cserr HF, Knopf PM . Cervical lymphatics, the blood–brain barrier and immunoreactivity of the brain: a new view Immunol Today 1992 13: 507–512

    Article  CAS  PubMed  Google Scholar 

  31. Fabry Z, Raine CS, Hart MN . Nervous tissue as an immune compartment: the dialect of the immune response in the CNS Immunol Today 1994 15: 218–224

    Article  CAS  PubMed  Google Scholar 

  32. Stevenson PG, Hawke S, Sloan DJ, Bangham RM . The immunogenicity of intracerebral virus infection depends on anatomical site J Virol 1997 71: 145–151

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Knopf PM et al. Antigen-dependent intrathecal antibody synthesis in the normal rat brain: tissue entry and local retention of antigen-specific B cells J Immunol 1998 161: 692–701

    CAS  PubMed  Google Scholar 

  34. Dewey RA et al. Chronic brain inflammation and persistent herpes simplex virus 1 thymidine kinase expression in survivors of syngeneic glioma treated by adenovirus-mediated gene therapy: implications for clinical trials Nature Med 1999 5: 1256–1263

    Article  CAS  PubMed  Google Scholar 

  35. Spergel JM, Chen-Kiang S . Interleukin 6 enhances a cellular activity that functionally substitutes for E1A protein in transactivation Proc Natl Acad Sci USA 1991 88: 6472–6476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Vincent AJPE et al. Herpes simplex virus thymidine kinase gene therapy for rat malignant brain tumors Hum Gene Ther 1996 7: 197–205

    Article  CAS  PubMed  Google Scholar 

  37. Precious B, Russel W . Growth, purification and titration of adenoviruses. In: Mahy B (ed) Virology: A Practical Approach Raven Press: New York 1985 pp 157–167

    Google Scholar 

  38. Fallaux FJ 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 

  39. Bout A et al. In vivo adenovirus-mediated transfer of human CFTR cDNA to rhesus monkey airway epithelium: efficacy, toxicity and safety Gene Therapy 1994 1: 385–394

    CAS  PubMed  Google Scholar 

  40. De Jong JC et al. Detection, typing and subtyping of enteric adenoviruses 40 and 41 from fecal samples and observation of changing incidences of infections with these types and subtypes J Clin Microbiol 1993 31: 1562–1569

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Snider R, Lee J . A Stereotactic Atlas of the Monkey Brain (Macaca mulatta) University of Chicago Press: Chicago, London 1961

    Google Scholar 

  42. McCully CL et al. A rhesus monkey model for continuous infusion of drugs into cerebrospinal fluid Lab An Sci 1990 40: 520–525

    CAS  Google Scholar 

  43. Fishman RA . Cerebrospinal fluid in diseases of the nervous system, (2nd edn.) WB Saunders Co: Philadelphia 1992

    Google Scholar 

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Acknowledgements

We thank J van Loon for the careful preparation of the histological sections. We are grateful to P van Eerd, H Koning and E Kuhn for their assistance in animal care and necropsies. This work was supported by the Nederlandse Hersenstichting.

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Authors and Affiliations

  1. Department of Neurosurgery, University Hospital Rotterdam, The Netherlands

    M J Driesse & C J J Avezaat

  2. IntroGene BV, Leiden, The Netherlands

    M C Esandi, D Valerio & A Bout

  3. Department of Neuropathology, University Hospital Rotterdam, The Netherlands

    J M Kros

  4. Department of Neuro-oncology, University Hospital Rotterdam, The Netherlands

    ChJ Vecht & P AE Sillevis Smitt

  5. Department of Veterinary Medicine, University of Utrecht, The Netherlands

    C Zurcher

  6. Department of Molecular Cell Biology, University of Leiden, The Netherlands

    I van der Velde & D Valerio

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  1. M J Driesse
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Driesse, M., Esandi, M., Kros, J. et al. Intra-CSF administered recombinant adenovirus causes an immune response-mediated toxicity. Gene Ther 7, 1401–1409 (2000). https://doi.org/10.1038/sj.gt.3301250

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