title: IL12-mediated liver inflammation reduces the formation of AAV transcriptionally active forms but has no effect over preexisting AAV transgene expression.
abstract: Recombinant adenoassociated viral vectors (rAAV) have proven to be excellent candidates for gene therapy clinical applications. Recent results showed that cellular immunity to AAV represents a major challenge facing the clinical use of systemic administration of these vectors. Interestingly, no preclinical animal model has previously fully reproduced the clinical findings. The aim of the present work was to enhance the T cell immune response against AAV capsid in mice by the administration of a rAAV expressing the immunostimulatory cytokine IL-12. Our results indicate that although IL-12 expression enhanced the AAV capsid-specific immune response it failed to eliminate transduced hepatocytes and long-term expression was achieved. We found that AAV-mediated transgene expression is altered by IL-12-induced liver inflammation. However, IL-12 expression has no effect over preexisting AAV-mediated transgene expression. IL-12 down-regulates AAV mediated transgene expression via induction of IFN-γ production by NK and T cells, but without altering the transduction efficiency measured by viral genomes. Our results indicate that liver inflammation affects the formation of transcriptionally active AAV vector genomes through an unknown mechanism that can be avoided by the use of DNA-demethylating or anti-inflammatory agents.
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research, Pamplona, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Gil-Fariña
authors.forename: Marianna
authors.initials: M
authors.lastname: Di Scala
authors.forename: Lucia
authors.initials: L
authors.lastname: Vanrell
authors.forename: Cristina
authors.initials: C
authors.lastname: Olagüe
authors.forename: Africa
authors.initials: A
authors.lastname: Vales
authors.forename: Katherine A
authors.initials: KA
authors.lastname: High
authors.forename: Jesus
authors.initials: J
authors.lastname: Prieto
authors.forename: Federico
authors.initials: F
authors.lastname: Mingozzi
authors.forename: Gloria
authors.initials: G
authors.lastname: Gonzalez-Aseguinolaza
mesh_terms: D000818:Animals; D002213:Capsid / Q000276:immunology; D000229:Dependovirus / Q000235:genetics / Q000276:immunology*; D005260:Female; D015870:Gene Expression / Q000276:immunology*; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000276:immunology; D022781:Hepatocytes / Q000276:immunology* / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology; D008099:Liver / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D014158:Transcription, Genetic / Q000276:immunology*; D019076:Transgenes / Q000276:immunology
chemical_list: D011993:Recombinant Fusion Proteins; D018664:Interleukin-12; D007371:Interferon-gamma