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.

  • Acquired Diseases
  • Published:

Transient control of a virus-induced immunopathology by genetic immunosuppression

Abstract

The ability to control T cell reactivity using suicide genes opens new perspectives for the treatment of T cell-mediated diseases. The therapeutic effect is achieved by the selective killing of thymidine kinase gene-modified activated T cells by ganciclovir (GCV). This strategy has been shown to control T cell alloreactivity efficiently after bone marrow or solid organ transplantation. Here, we aimed to determine whether an immunopathological process induced by a viral infection could be controlled by GCV when T cells express a thymidine kinase transgene. When transgenic mice were infected with the lymphocytic choriomeningitis virus, administration of GCV resulted in an efficient, but only transient, control of the immunopathological immune response. Further analysis revealed the existence of a minute population of GCV-insensitive T cells. These cells expand in response to the virus despite the presence of GCV and cause immunopathology before viral elimination is finally obtained. Thus, when confronted with a replicative virus, the efficacy of this genetic immunosuppression strategy is highly dependent on the presence of even small numbers of GCV-insensitive cells. These results emphasize the need for sufficient preclinical investigations with regard to the pathology and the nature of the immune response if suicide gene transfer is envisioned for new therapeutic indications.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Moolten FL . Drug sensitivity (‘suicide’) genes for selective cancer chemotherapy Cancer Gene Ther 1994 1: 279–287

    CAS  PubMed  Google Scholar 

  2. Nishiyama Y, Rapp F . Anticellular effects of 9-(2-hydroxyethoxymethyl) guanine against herpes simplex virus-transformed cells J Gen Virol 1979 45: 227–230

    Article  CAS  PubMed  Google Scholar 

  3. St. Clair MH, Lambe CU, Furman PA . Inhibition by ganciclovir of cell growth and DNA synthesis of cells biochemically transformed with herpesvirus genetic information Antimicrob Agents Chemother 1987 31: 844–849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Moolten F . Tumor sensitivity conferred by inserted herpes thymidine kinase genes: paradigm for prospective cancer control strategy Cancer Res 1986 46: 5276–5281

    CAS  PubMed  Google Scholar 

  5. Culver K et al. In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors Science 1992 256: 1550–1552

    Article  CAS  PubMed  Google Scholar 

  6. Caruso M et al. Regression of established macroscopic liver metastases after in situ transduction of a suicide gene Proc Natl Acad Sci USA 1993 90: 7024–7028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Anonymous . Human gene marker/therapy clinical protocols Hum Gene Ther 1999 10: 2037–2088

    Article  Google Scholar 

  8. Heyman RA et al. Thymidine kinase obliteration: creation of transgenic mice with controlled immune deficiency Proc Natl Acad Sci USA 1989 86: 2698–2702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Minasi LE et al. The selective ablation of interleukin 2-producing cells isolated from transgenic mice J Exp Med 1993 177: 1451–1459

    Article  CAS  PubMed  Google Scholar 

  10. Dzierzak E et al. Thy-1 tk transgenic mice with a conditional lymphocyte deficiency Int Immunol 1993 5: 975–984

    Article  CAS  PubMed  Google Scholar 

  11. Salomon B et al. Conditional ablation of dendritic cells in transgenic mice J Immunol 1994 152: 537–548

    CAS  PubMed  Google Scholar 

  12. Cohen JL et al. Prevention of graft-versus-host disease in mice using a suicide gene expressed in T lymphocytes Blood 1997 89: 4636–4645

    CAS  PubMed  Google Scholar 

  13. Helene M et al. Inhibition of graft-versus-host disease. Use of a T cell-controlled suicide gene J Immunol 1997 158: 5079–5082

    CAS  PubMed  Google Scholar 

  14. Bordignon C et al. Transfer of the HSV-tk gene into donor peripheral blood lymphocytes for in vivo modulation of donor anti-tumor immunity after allogeneic bone marrow transplantation Hum Gene Ther 1995 6: 813–819

    Article  CAS  PubMed  Google Scholar 

  15. Bonini C et al. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia Science 1997 276: 1719–1724

    Article  CAS  PubMed  Google Scholar 

  16. Tiberghien P et al. Use of donor T-lymphocytes expressing herpes-simplex thymidine kinase in allogeneic bone marrow transplantation: a phase I–II study Hum Gene Ther 1997 8: 615–624

    Article  CAS  PubMed  Google Scholar 

  17. Link CJ Jr et al. Adoptive immunotherapy for leukemia: donor lymphocytes transduced with the herpes simplex thymidine kinase gene for remission induction Hum Gene Ther 1998 9: 115–134

    Article  PubMed  Google Scholar 

  18. Mavilio F et al. Peripheral blood lymphocytes as target cells of retroviral vector-mediated gene transfer Blood 1994 83: 1988–1997

    CAS  PubMed  Google Scholar 

  19. Tiberghien P et al. Ganciclovir treatment of herpes simplex thymidine kinase-transduced primary T lymphocytes: an approach for specific in vivo donor T-cell depletion after bone marrow transplantation? Blood 1994 84: 1333–1341

    CAS  PubMed  Google Scholar 

  20. Munshi NC et al. Thymidine kinase (TK) gene-transduced human lymphocytes can be highly purified, remain fully functional, and are killed efficiently with ganciclovir Blood 1997 89: 1334–1340

    CAS  PubMed  Google Scholar 

  21. Braunberger E et al. Tolerance induced without immunosuppression in a T-lymphocyte suicide-gene therapy cardiac allograft model in mice J Thorac Cardiovasc Surg 2000 119: 46–51

    Article  CAS  PubMed  Google Scholar 

  22. Buchmeier MJ, Welsh RM, Dutko FJ, Oldstone MB . The virology and immunobiology of lymphocytic choriomeningitis virus infection Adv Immunol 1980 30: 275–331

    Article  CAS  PubMed  Google Scholar 

  23. Allan JE, Dixon JE, Doherty PC . Nature of the inflammatory process in the central nervous system of mice infected with lymphocytic choriomeningitis virus Curr Top Microbiol Immunol 1987 134: 131–143

    CAS  PubMed  Google Scholar 

  24. Kagi D et al. Molecular mechanisms of lymphocyte-mediated cytotoxicity and their role in immunological protection and pathogenesis in vivo Annu Rev Immunol 1996 14: 207–232

    Article  CAS  PubMed  Google Scholar 

  25. Moskophidis D, Assmann-Wischer U, Simon MM, Lehmann-Grube F . The immune response of the mouse to lymphocytic choriomeningitis virus. V. High numbers of cytolytic T lymphocytes are generated in the spleen during acute infection Eur J Immunol 1987 17: 937–942

    Article  CAS  PubMed  Google Scholar 

  26. Zinkernagel RM, Doherty PC . Cytotoxic thymus-derived lymphocytes in cerebrospinal fluid of mice with lymphocytic choriomeningitis J Exp Med 1973 138: 1266–1269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Saron MF, Guillon JC . Evidence for the presence of T lymphocytes mediating lymphocytic choriomeningitis virus-specific delayed-type hypersensitivity in meningeal infiltrates of infected mice Ann Virol Inst Pasteur 1983 134 E: 309–314

    Article  Google Scholar 

  28. Thomsen AR, Bro-Jorgensen K, Volkert M . Fatal meningitis following lymphocytic choriomeningitis virus infection reflects delayed-type hypersensitivity rather than cytotoxicity Scand J Immunol 1983 17: 139–145

    Article  CAS  PubMed  Google Scholar 

  29. Christoffersen PJ, Volkert M, Rygaard J . Immunological unresponsiveness of nude mice to LCM virus infection Acta Pathol Microbiol Scand [C] 1976 84C: 520–523

    CAS  Google Scholar 

  30. Fung-Leung WP, Kündig TM, Zinkernagel RM, Mak TW . Immune response against lymphocytic choriomeningitis virus infection in mice without CD8 expression J Exp Med 1991 174: 1425–1429

    Article  CAS  PubMed  Google Scholar 

  31. Lehmann-Grube F, Löhler J, Utermöhlen O, Gegin C . Antiviral immune responses of lymphocytic choriomeningitis virus-infected mice lacking CD8+ T lymphocytes because of disruption of the β2-microglobulin gene J Virol 1993 67: 332–339

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Rahemtulla A et al. Normal development and function of CD8+ cells but markedly decreased helper cell activity in mice lacking CD4 Nature 1991 353: 180–184

    Article  CAS  PubMed  Google Scholar 

  33. Christensen JP, Marker O, Thomsen AR . The role of CD4+ T cells in cell-mediated immunity to LCMV: studies in MHC class I and class II deficient mice Scand J Immunol 1994 40: 373–382

    Article  CAS  PubMed  Google Scholar 

  34. Battegay M et al. Enhanced establishment of a virus carrier state in adult CD4+ T-cell-deficient mice J Virol 1994 68: 4700–4704

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Tosolini FA, Mims CA . Effect of murine strain and viral strain on the pathogenesis of lymphocytic choriomeningitis infection and a study of footpad responses J Infect Dis 1971 123: 134–144

    Article  CAS  PubMed  Google Scholar 

  36. Assmann-Wischer U, Simon MM, Lehmann-Grube F . Mechanism of recovery from acute virus infection. III. Subclass of T lymphocytes mediating clearance of lymphocytic choriomeningitis virus from the spleens of mice Med Microbiol Immunol (Berl) 1985 174: 249–256

    Article  CAS  Google Scholar 

  37. Moskophidis D et al. Virus-specific delayed-type hypersensitivity (DTH). Cells mediating lymphocytic choriomeningitis virus-specific DTH reaction in mice J Immunol 1990 144: 1926–1934

    CAS  PubMed  Google Scholar 

  38. Cohen JL et al. Fertile homozygous transgenic mice expressing a functional truncated Herpes simplex thymidine kinase ΔTK gene Transgenic Res 1998 7: 321–330

    Article  CAS  PubMed  Google Scholar 

  39. Salmon P et al. Characterization of an intronless CD4 minigene expressed in mature CD4 and CD8 T cells, but not expressed in immature thymocytes J Immunol 1996 156: 1873–1879

    CAS  PubMed  Google Scholar 

  40. Faulds D, Heel RC . Ganciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in cytomegalovirus infections Drugs 1990 39: 597–638

    Article  CAS  PubMed  Google Scholar 

  41. Paul S, Dummer S . Topics in clinical pharmacology: ganciclovir Am J Med Sci 1992 304: 272–277

    Article  CAS  PubMed  Google Scholar 

  42. Dobie KW et al. Variegated transgene expression in mouse mammary gland is determined by the transgene integration locus Proc Natl Acad Sci USA 1996 93: 6659–6664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Festenstein R et al. Locus control region function and heterochromatin-induced position effect variegation Science 1996 271: 1123–1125

    Article  CAS  PubMed  Google Scholar 

  44. Boyer O et al. Position-dependent variegation of a CD4 minigene with targeted expression to mature CD4+ T cells J Immunol 1997 159: 3383–3390

    CAS  PubMed  Google Scholar 

  45. Cohen JL, Boyer O, Klatzmann D . Would suicide gene therapy solve the T-cell dilemma of allogeneic bone marrow transplantation? Immunol Today 1999 20: 172–176

    Article  CAS  PubMed  Google Scholar 

  46. Cohen JL et al. Immunological defects after suicide gene therapy of experimental graft-versus-host disease Hum Gene Ther 1999 10: 2701–2707

    Article  CAS  PubMed  Google Scholar 

  47. Cohen JL, Boyer O, Thomas-Vaslin V, Klatzmann D . Suicide-gene mediated modulation of graft-versus-host disease Leuk Lymphoma 1999 34: 473–480

    Article  CAS  PubMed  Google Scholar 

  48. Thomas-Vaslin V et al. Prolonged allograft survival through conditional and specific ablation of alloreactive T-cells expressing a suicide gene Transplantation 2000 69: 2154–2161

    Article  CAS  PubMed  Google Scholar 

  49. Movassagh M et al. Retrovirus-mediated gene transfer into T-cells: 95% transduction efficiency without further in vitro selection Hum Gene Ther 2000 11: 1189–1200

    Article  CAS  PubMed  Google Scholar 

  50. Roger F, Hotchin J . Local reactivity of lymphocytic choriomeningitis virus in the mouse: its development as a new diagnosis test Ann Rep Div Lab Res NY State Dpt Health 1961 43–44

  51. Marrie TJ, Saron MF . Seroprevalence of lymphocytic choriomeningitis virus in Nova Scotia Am J Trop Med Hyg 1998 58: 47–49

    Article  CAS  PubMed  Google Scholar 

  52. Battegay M et al. Quantification of lymphocytic choriomeningitis virus with an immunological focus assay in 24- or 96-well plates J Virol Methods 1991 33: 191–198

    Article  CAS  PubMed  Google Scholar 

  53. Okuno Y et al. Rapid focus reduction neutralization test of Japanese encephalitis virus in microtiter system. Brief report Arch Virol 1985 86: 129–135

    Article  CAS  PubMed  Google Scholar 

  54. Park JY et al. Development of a reverse transcription-polymerase chain reaction assay for diagnosis of lymphocytic choriomeningitis virus infection and its use in a prospective surveillance study J Med Virol 1997 51: 107–114

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We wish to acknowledge C Leclerc for providing monoclonal antibodies for in vivo depletion, L Lejeune, J Foulon and B Clerc for technical assistance, A Membrillera- Pizarro for animal care and A Mallet for help with the statistical analysis. This work was supported in part by the ‘Université Pierre et Marie Curie’, the ‘Agence Nationale de Recherche contre le SIDA’, the ‘Association de Recherche sur les Déficits Immunitaires Viro-Induits Génopoiétic’ and the ‘Centre National de la Recherche Scientifique’.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Boyer, O., Cohen, J., Bellier, B. et al. Transient control of a virus-induced immunopathology by genetic immunosuppression. Gene Ther 7, 1536–1542 (2000). https://doi.org/10.1038/sj.gt.3301276

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3301276

Keywords

Search

Quick links