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  • Acquired Diseases
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Adeno-associated virus-mediated delivery of IL-4 prevents collagen-induced arthritis

Gene Therapy volume 7, pages 1930–1939 (2000)Cite this article

Abstract

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 × 1010 or 11.2 × 1010AAV-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.

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Acknowledgements

We would like to thank Mariane Ziol (UPRES EA-2361) for assistance with histology processing, Patrick Nicolas, Roger Vassy (UPRES EA-2360), Alexandre Megnigbeto and Christian Portafax (University of Paris XIII) for their expert advice in statistics. We are grateful to Delphine Lemeiter, Monique Etienne and Simone Beranger for their outstanding technical assistance and to Stéphane Chambris for his expert care of the animals. This work was supported by two French nonprofit organizations, the ‘Association de Recherche sur la Polyarthrite’ and the ‘Société Française de Rhumatologie’. We thank the Production Service Unit of Genethon III for providing AAV vectors in the frame of the Gene Vector Production Network (GVPN, http://www.genethon.fr/gvpn) supported by the Association Française contre les Myopathies (AFM, Evry, France).

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Authors and Affiliations

  1. UPRES EA-2361, UFR Léonard de Vinci, Université Paris XIII, Bobigny, and Groupe de Recherche en Immunopathologie et Immuno-intervention de l'Association Claude Bernard, France

    V Cottard, D Mulleman, M-C Boissier & N Bessis

  2. Genethon III, URA 1923 CNRS, Evry, France

    P Bouille & M Mezzina

  3. Rheumatology Department, Hopital Avicenne, Bobigny, France

    M-C Boissier

  4. INSERM U477, Université René Descartes, Paris, France

    M-C Boissier & N Bessis

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  2. D Mulleman
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Cottard, V., Mulleman, D., Bouille, P. et al. Adeno-associated virus-mediated delivery of IL-4 prevents collagen-induced arthritis. Gene Ther 7, 1930–1939 (2000). https://doi.org/10.1038/sj.gt.3301324

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