Abstract
Hepatitis C virus (HCV)-induced, end-stage liver disease is a major indication for liver transplantation, but systematic graft reinfection accelerates liver disease recurrence. Transplantation recipients may be ineligible for direct-acting antivirals, owing to toxicity, resistance or advanced liver disease. Adoptive immunotherapy with liver graft-derived, ex vivo-activated lymphocytes was previously shown to prevent HCV-induced graft reinfections. Alternatively, the applicability and therapeutic efficacy of adoptive immunotherapy may be enhanced by ‘ready for use’ suicide gene-modified lymphocytes from healthy blood donors; moreover, conditional, prodrug-induced cell suicide may prevent potential side effects. Here, we demonstrate that allogeneic suicide gene-modified lymphocytes (SGMLs) could potently, dose- and time-dependently, inhibit viral replication. The effect occurs at effector:target cell ratios that exhibits no concomitant cytotoxicity toward virus-infected target cells. The effect, mediated mostly by CD56+ lymphocytes, is interleukin-2-dependent, IFN-γ-mediated and, importantly, resistant to calcineurin inhibitors. Thus, post-transplant immunosuppression may not interfere with this adoptive cell immunotherapy approach. Furthermore, these cells are indeed amenable to conditional cell suicide; in particular, the inducible caspase 9 suicide gene is superior to the herpes simplex virus thymidine kinase suicide gene. Our data provide in vitro proof-of-concept that allogeneic, third-party, SGMLs may prevent HCV-induced liver graft reinfection.
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Acknowledgements
This study was supported by Inserm, the Fondation pour la Recherche Médicale (Comité Alsace), the Ligue Nationale Contre le Cancer (Conférence de Coordination Inter-Régionale Grand-Est, grant # 1FI10005LBKD), the Association pour la recherche sur le Cancer (ARC, grant # SFI20111203529), the Société d’Accélération de Transfert de Technologie (SATT) Conectus Alsace, the Agence Nationale pour la Recherche (ANR, LabEx program) and EU Interreg-IV Program Hepato-Regio-Net. Eric Robinet was supported by the Agence Nationale pour la Recherche sur le SIDA et les Hépatites Virales (ANRS, grant # 2008 059 ULP). Céline Leboeuf received fellowships from the Fondation Transplantation and the Association pour la Recherche sur le Cancer (ARC, grant # DOC20110603384); and Tao Wu received a fellowship from the Alsace Region. A European Patent application (n° EP12305259.9) related to this study, entitled ‘Method for preventing or treating HCV infection by administration of suicide gene-modified lymphocytes’, was submitted on the 2 March 2012 by the University of Strasbourg.
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Leboeuf, C., Roser-Schilder, J., Lambotin, M. et al. Prevention of hepatitis C virus infection by adoptive allogeneic immunotherapy using suicide gene-modified lymphocytes: an in vitro proof-of-concept. Gene Ther 22, 172–180 (2015). https://doi.org/10.1038/gt.2014.99
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DOI: https://doi.org/10.1038/gt.2014.99