Immune responses, not promoter inactivation, are responsible for decreased long-term expression following plasmid gene transfer into skeletal muscle.
Long-term high-level in vivo gene expression appears to depend on the promoter chosen to drive the gene of choice. In many cases the promoter appears to 'switch off' some time after in vivo gene transfer. We demonstrate that, following intramuscular injection of beta-galactosidase reporter plasmids, promoter 'switch off' is due to elimination of fibres expressing the transferred reporter gene by activation of a Th1 (cytotoxic) immune response. This finding, in the absence of stimulation of the immune system by viral vector proteins, has implications not only for gene transfer experiments but for the future of muscle-directed gene therapy.
Wells
K E
KE
Department of Pharmacology, Charing Cross and Westminster Medical School, London, UK.
Maule
J
J
Kingston
R
R
Foster
K
K
McMahon
J
J
Damien
E
E
Poole
A
A
Wells
D J
DJ
D000818:Animals; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D007132:Immunoglobulin Isotypes / Q000097:blood; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D018482:Muscle, Skeletal / Q000276:immunology* / Q000473:pathology; D011994:Recombinant Proteins / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D001616:beta-Galactosidase / Q000235:genetics / Q000276:immunology
D007132:Immunoglobulin Isotypes; D011994:Recombinant Proteins; D015500:Chloramphenicol O-Acetyltransferase; D001616:beta-Galactosidase