Tetracycline-inducible interleukin-10 gene transfer mediated by an adeno-associated virus: application to experimental arthritis.
The adeno-associated viruses (AAV) offer new perspectives for cytokine gene transfer in rheumatoid arthritis (RA) because they are nonpathogenic and allow long-term transgene expression in vivo. Moreover, the use of a tetracycline-inducible promoter allows regulation of therapeutic gene expression. This study assessed the potential long-term gene regulation of a recombinant AAV vector expressing viral interleukin-10 (vIL-10) in human rheumatoid synovium and the therapeutic efficiency in a mouse model of RA. We constructed a recombinant AAV vector in which the transcription of vIL-10 cDNA is controlled by the TetON system. Transduction of human primary RA synovial cells with AAV-tetON-vIL10 conferred in vitro controlled vIL-10 expression. After intramuscular injection, both incidence and severity of collagen-induced arthritis were significantly reduced at macroscopic, radiological, and histological levels in the group of DBA1 mice treated with AAV-TetON-vIL10 vector plus doxycycline after immunization and boosting compared to control groups. When coinjecting two separate AAV vectors, one encoding the inducible vIL-10 and the other the transcriptional activator, a 10 times excess of the transactivator vector dose allowed efficient control of vIL-10 secretion by doxycycline administration or withdrawal, over an 8-week period. Our results supported, for the first time, the utility of AAV-tetON-vIL10 as a therapeutic tool for gene therapy in RA.
Unité de Recherche en Immunopathologie des Maladies Tumorales et Autoimmunes, INSERM U475, France. appara@montp.inserm.fr
Florence
F
Apparailly
Virginie
V
Millet
Daniele
D
Noël
Chantal
C
Jacquet
Jacques
J
Sany
Christian
C
Jorgensen
D000818:Animals; D001169:Arthritis, Experimental / Q000628:therapy*; D000229:Dependovirus / Q000235:genetics*; D015870:Gene Expression; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D016679:Genome, Viral; D006367:HeLa Cells; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009928:Organ Specificity; D013752:Tetracycline / Q000494:pharmacology*
D016753:Interleukin-10; D013752:Tetracycline