Prevention of hepatitis C virus infection by adoptive allogeneic immunotherapy using suicide gene-modified lymphocytes: an in vitro proof-of-concept
| Autor: | Eric Robinet, Christophe Ferrand, Marina Deschamps, J Roser-Schilder, Sarah C. Durand, Patrick Pessaux, T Wu, Catherine Fauvelle, Pierre Tiberghien, M Lambotin, Thomas F. Baumert, Céline Leboeuf, Elodie Bole-Richard, B Su |
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| Rok vydání: | 2014 |
| Předmět: |
medicine.medical_treatment
Hepatitis C virus Hepacivirus Biology Liver transplantation Virus Replication medicine.disease_cause Immunotherapy Adoptive Liver disease Cell Line Tumor Genetics medicine Humans Transplantation Homologous Lymphocytes Molecular Biology Immunosuppression Genetic Therapy Immunotherapy Hepatitis C Suicide gene medicine.disease Caspase 9 Transplantation Immunology Molecular Medicine |
| Zdroj: | Gene Therapy. 22:172-180 |
| ISSN: | 1476-5462 0969-7128 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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