Prevention of hepatitis C virus infection by adoptive allogeneic immunotherapy using suicide gene-modified lymphocytes: an in vitro proof-of-concept.
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.
1] Inserm, UMR 1110, Strasbourg, France [2] Université de Strasbourg, Strasbourg, France.
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Leboeuf
1] Inserm, UMR 1110, Strasbourg, France [2] Université de Strasbourg, Strasbourg, France.
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Roser-Schilder
1] Inserm, UMR 1110, Strasbourg, France [2] Université de Strasbourg, Strasbourg, France.
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Lambotin
1] Inserm, UMR 1110, Strasbourg, France [2] Université de Strasbourg, Strasbourg, France.
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Durand
1] Inserm, UMR 1110, Strasbourg, France [2] Université de Strasbourg, Strasbourg, France [3] Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China.
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Wu
1] Inserm, UMR 1110, Strasbourg, France [2] Université de Strasbourg, Strasbourg, France.
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Fauvelle
1] Inserm, UMR 1110, Strasbourg, France [2] Université de Strasbourg, Strasbourg, France.
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Su
1] Etablissement Français du Sang Bourgogne/Franche-Comté, UMR 1098, Besançon, France [2] Inserm, UMR 1098, Besançon, France [3] Université de Franche-Comté, UMR 1098, Besançon, France.
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Bôle-Richard
1] Etablissement Français du Sang Bourgogne/Franche-Comté, UMR 1098, Besançon, France [2] Inserm, UMR 1098, Besançon, France [3] Université de Franche-Comté, UMR 1098, Besançon, France.
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Deschamps
1] Etablissement Français du Sang Bourgogne/Franche-Comté, UMR 1098, Besançon, France [2] Inserm, UMR 1098, Besançon, France [3] Université de Franche-Comté, UMR 1098, Besançon, France.
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Ferrand
1] Etablissement Français du Sang Bourgogne/Franche-Comté, UMR 1098, Besançon, France [2] Inserm, UMR 1098, Besançon, France [3] Université de Franche-Comté, UMR 1098, Besançon, France.
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Tiberghien
1] Inserm, UMR 1110, Strasbourg, France [2] Université de Strasbourg, Strasbourg, France [3] Pôle Hépatodigestif, Nouvel Hopital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France [4] Institut Hospitalo-Universitaire de Strasbourg, Strasbourg, France.
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Pessaux
1] Inserm, UMR 1110, Strasbourg, France [2] Université de Strasbourg, Strasbourg, France [3] Pôle Hépatodigestif, Nouvel Hopital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
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Baumert
1] Inserm, UMR 1110, Strasbourg, France [2] Université de Strasbourg, Strasbourg, France [3] Institut Hospitalo-Universitaire de Strasbourg, Strasbourg, France.
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Robinet
D053453:Caspase 9 / Q000235:genetics; D045744:Cell Line, Tumor; D015316:Genetic Therapy; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000517:prevention & control*; D006801:Humans; D016219:Immunotherapy, Adoptive; D008214:Lymphocytes / Q000502:physiology*; D014184:Transplantation, Homologous; D014779:Virus Replication
C506433:CASP9 protein, human; D053453:Caspase 9