Adeno-associated virus-mediated delivery of IL-4 prevents collagen-induced arthritis.
Immunomodulation of autoimmune inflammatory diseases like rheumatoid arthritis can be achieved by anti-inflammatory T2 cytokines such as interleukin (IL)-4 administered by gene therapy. In this study we investigated the efficiency of adeno-associated viruses (AAV) vectors in collagen-induced arthritis (CIA). After injection of AAV-LacZ in the tarsus area of mice, the expression of the transgene was localized in the deep muscles cells near the bone. LacZ expression was found in liver, heart and lung after i.m. injection of AAV-LacZ, showing a spread of the vector over the body. Anti-AAV neutralizing antibodies were detected in the serum after i.m. injection of AAV-LacZ, but they did not alter the transgene expression after re-administration of AAV-LacZ. Long-term IL-4 expression persisted 129 days after intra-muscular injection of 3.7 x 10(10) or 11.2 x 10(10) AAV-IL-4 p.p. (average 7.7 or 17.5 pg IL-4/mg proteins, respectively). More importantly, the treatment of CIA with AAV-IL-4 vector in mice produced a therapeutic benefit, since we show a diminished prevalence of the disease, a significant reduction in paw swelling, attenuated histological synovitis and a 10 days delayed onset of arthritis. This is the first evidence that AAV vector-mediated gene therapy using a T2 cytokine is efficient in an animal model of rheumatoid arthritis.
Cottard
V
V
UPRES EA-2361, UFR Léonard de Vinci, Université Paris XIII, Bobigny, France.
Mulleman
D
D
Bouille
P
P
Mezzina
M
M
Boissier
M C
MC
Bessis
N
N
D000704:Analysis of Variance; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000517:prevention & control*; D003094:Collagen; D000229:Dependovirus / Q000235:genetics*; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D007273:Injections, Intramuscular; D015847:Interleukin-4 / Q000008:administration & dosage / Q000235:genetics*; D007763:Lac Operon; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D015847:Interleukin-4; D003094:Collagen