Prevention of hepatitis C virus infection by adoptive allogeneic immunotherapy using suicide gene-modified lymphocytes: an in vitro proof-of-concept

• Published in: Gene therapy 2015-02, Vol.22 (2), p.172-180
• Main Authors: Leboeuf, C, Roser-Schilder, J, Lambotin, M, Durand, S, Wu, T, Fauvelle, C, Su, B, Bôle-Richard, E, Deschamps, M, Ferrand, C, Tiberghien, P, Pessaux, P, Baumert, T F, Robinet, E
• Format: Article
• Language: English
• Subjects: 631/250/251; Adoptive immunotherapy; Antiviral agents; Biomedical and Life Sciences; Biomedicine; Blood donors; Calcineurin; Calcineurin inhibitors; Caspase 9 - genetics; Caspase-9; CD56 antigen; Cell Biology; Cell Line, Tumor; Cytotoxicity; Disease resistance; Gene Expression; Gene Therapy; Genetic aspects; Genetic Therapy; Health aspects; Hepacivirus - immunology; Hepatitis; Hepatitis C; Hepatitis C - prevention & control; Hepatitis C virus; Herpes simplex; Herpes simplex virus; Human Genetics; Human health and pathology; Humans; Immunosuppression; Immunotherapy; Immunotherapy, Adoptive; Interleukin 2; Life Sciences; Liver diseases; Liver transplantation; Lymphocytes; Lymphocytes - physiology; Methods; Nanotechnology; original-article; Prevention; Suicide genes; Thymidine; Thymidine kinase; Transplantation, Homologous; Transplants & implants; Virus Replication; γ-Interferon
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2014.99

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.