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- Title
Prevention of hepatitis C virus infection by adoptive allogeneic immunotherapy using suicide gene-modified lymphocytes: an in vitro proof-of-concept.
- 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
- 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.
- Subjects
HEPATITIS C prevention; IMMUNOTHERAPY; GRAFT versus host disease; LYMPHOCYTES; IN vitro studies; CHRONIC kidney failure; ANTIVIRAL agents; THERAPEUTICS
- Publication
Gene Therapy, 2015, Vol 22, Issue 2, p172
- ISSN
0969-7128
- Publication type
Article
- DOI
10.1038/gt.2014.99