Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Gene transfer through the blood–nerve barrier: NGF-engineered neuritogenic T lymphocytes attenuate experimental autoimmune neuritis

Nature Medicine volume 1, pages 1162–1166 (1995)Cite this article

Abstract

Nerve-specific autoimmune T lymphocytes were used as vehicles to deliver therapeutically useful neurotrophic factors across the endothelial blood–nerve barrier. P2 protein-reactive T-lymphocyte lines from Lewis rats were transduced with a recombinant retrovirus containing the mouse nerve growth factor (NGF) gene. The engineered T cells released high amounts of NGF dependent on antigenic stimulation in vitro. After intravenous injection, the T cells infiltrated the rat peripheral nervous system and persisted there for at least two weeks. Local release of NGF from engineered T cells was demonstrable by immunocytochemistry and by an anti-inflammatory effect on infiltrating macrophages.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Linington, C. et al. A permanent rat T Cell line that mediates experimental allergic neuritis in the Lewis rat in vivo. J. Immun. 133, 1946–1950 (1984).

    CAS  PubMed  Google Scholar 

  2. Hartung, H.-P., StoII, G. & Toyka, K.V. Immune reactions in the peripheral nervous system. in Peripheral Neuropathy, 3rd edn (eds Dyck, P. J., Thomas, P.K., Griffin, J.W., Low, P.A. & Poduslo, J.F.) 418–462 (Saunders, Philadelphia, (1993).

    Google Scholar 

  3. Izumo, S., Linington, C., Wekerle, H. & Meyermann, R. Morphologic study of experimental allergic neuritis mediated by T-Cell line specific for bovine P2 protein in Lewis rats. Lab. Invest. 53, 209–218 (1985).

    CAS  PubMed  Google Scholar 

  4. Heininger, K., Stoll, G., Linington, C., Toyka, K.V. & Wekerle, H. Conduction failure and nerve conduction slowing in experimental autoimmune neuritis induced by P2-specific T Cell lines. Ann. Neural. 19, 44–49 (1986).

    Article  CAS  Google Scholar 

  5. Kawaja, M.D., Rosenberg, M.B., Yoshida, K. & Gage, F.H., Cell transfer of nerve growth factor promotes the survival of axotomized septal neurons and the regeneration of of their axons in adult rats. J. Neurosci. 12, 2849–2864 (1992).

    Article  CAS  Google Scholar 

  6. Cournoyer, D. & Caskey, C.T. Gene therapy of the immune system. Annu. Rev. Immun. 11, 297–329 (1993).

    Article  CAS  Google Scholar 

  7. Wekerle, H., Linington, C., Lassmann, H. & Meyermann, R. Cellular immune reactivity within the CNS. Trends Neurosci. 9, 271–277 (1986).

    Article  Google Scholar 

  8. Hwu, P. et al. Functional and molecular characterization of tumor-infiltrating lymphocytes transduced with tumor necrosis factor-cDNA for the gene therapy of cancer in humans. J. Immun. 150, 4104–4115 (1993).

    CAS  PubMed  Google Scholar 

  9. Lampert, P.W., Garret, R. & Powell, H.C. Demyelination in allergic and Marek's disease induced neuritis: Comparative electron microscopic studies. Acta Neuropath. 40, 103–110 (1977).

    Article  CAS  Google Scholar 

  10. Heininger, K. et al. The role of macrophages in experimental autoimmune neuritis induced by a P2-specific T-Cell line. Ann. Neurol. 23, 326–331 (1988).

    Article  CAS  Google Scholar 

  11. Sebert, M.E. & Shooter, E.M. Expression of mRNA for neurotrophic factors and their receptors in the rat dorsal root ganglion and sciatic nerve following nerve injury. J. Neurosci. Res. 36, 357–367 (1993).

    Article  CAS  Google Scholar 

  12. Ehrhard, P.B., Ganter, U., Bauer, J. & Otten, U. Expression of functional trk protooncogene in human monocytes. Proc. natn. Acad. Sci. U.S.A. 90, 5423–5427 (1993).

    Article  CAS  Google Scholar 

  13. Ehrhard, P.B., Erb, P., Graumann, U. & Otten, U. Expression of nerve growth factor and nerve growth factor receptor tyrosine kinase Trk in activated CD4-positive T-Cell clones. Proc. natn. Acad. Sci. U.S.A. 90, 10984–10988 (1993).

    Article  CAS  Google Scholar 

  14. Linington, C. et al. T Cell specific for the myelin oligodendrocyte glycoprotein (MOG) mediate an unusual autoimmune inflammatory response in the central nervous system. Eur. J. Immun. 23, 1364–1372 (1993).

    Article  CAS  Google Scholar 

  15. Scott, J. et al. Isolation and nucleotide sequence of a cDNA encoding the precursor of mouse nerve growth factor. Nature 302, 538–540 (1983).

    Article  CAS  Google Scholar 

  16. Miller, D. & Rosman, G. Improved retroviral vectors for gene transfer and expression. Bio Technique 7, 980–990 (1989).

    CAS  Google Scholar 

  17. Markowitz, D., Goff, S. & Bank, A. A safe packaging line for gene transfer: Separating viral genes on two different plasmids. J. Virol. 62, 1120–1124 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Chen, C. & Okayama, H. High-efficiency transformation of mammalian Cells by plasmid DNA. Molec. Cell Biol. 7, 2745–2752 (1987).

    Article  CAS  Google Scholar 

  19. Korsching, S. & Thoenen, H. Nerve growth factor in sympathetic ganglia and corresponding target organs of the rat: Correlation with density of sympathetic innervation. Proc. natn. Acad. Sci. U.S.A. 80, 3513–3516 (1983).

    Article  CAS  Google Scholar 

  20. Spranger, M. et al. Regulation of nerve growth factor (NGF) synthesis in the rat central nervous system: Comparison between the effects of interleukin-1 and various growth factors in astrocyte cultures and in vivo. Eur. J. Neurosci. 2, 69–76 (1990).

    Article  Google Scholar 

  21. Castrén, E., Zafra, F., Thoenen, H. & Lindholm, D. Light regulates expression of brain-derived neurotrophic factor mRNA in rat visual cortex. Proc. natn. Acad. Sci. U.S.A. 89, 9444–9448 (1992).

    Article  Google Scholar 

  22. Gehrmann, J. et al. Spinal cord microglia in experimental allergic neuritis: Evidence for fast and remote activation. Lab. Invest. 67, 100–113 (1992).

    CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Rainer Kramer and Yiping Zhang: The first two authors contributed equally to the work described in this paper. This work was supported by a grant from the Volkswagen Foundation to H.W. and Y.Z., and a scholarship from the Deutsche Forschungs-gemeinschaft to R.G.

Authors and Affiliations

  1. Max-Planck-Institute for Psychiatry, D–821S2, Martinsried, Germany

    Rainer Kramer, Yiping Zhang, Ralf Gold & Hans Thoenen

  2. Department of Pathology, University Hospital, CH–8091, Zurich, Switzerland

    Jochen Gehrmann

Authors
  1. Rainer Kramer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yiping Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jochen Gehrmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ralf Gold
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hans Thoenen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hartmut Wekerle
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kramer, R., Zhang, Y., Gehrmann, J. et al. Gene transfer through the blood–nerve barrier: NGF-engineered neuritogenic T lymphocytes attenuate experimental autoimmune neuritis. Nat Med 1, 1162–1166 (1995). https://doi.org/10.1038/nm1195-1162

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1195-1162

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing