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