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IL4 gene delivery to the CNS recruits regulatory T cells and induces clinical recovery in mouse models of multiple sclerosis

Gene Therapy volume 15, pages 504–515 (2008)Cite this article

Abstract

Central nervous system (CNS) delivery of anti-inflammatory cytokines, such as interleukin 4 (IL4), holds promise as treatment for multiple sclerosis (MS). We have previously shown that short-term herpes simplex virus type 1-mediated IL4 gene therapy is able to inhibit experimental autoimmune encephalomyelitis (EAE), an animal model of MS, in mice and non-human primates. Here, we show that a single administration of an IL4-expressing helper-dependent adenoviral vector (HD-Ad) into the cerebrospinal fluid (CSF) circulation of immunocompetent mice allows persistent transduction of neuroepithelial cells and long-term (up to 5 months) CNS transgene expression without toxicity. Mice affected by chronic and relapsing EAE display clinical and neurophysiological recovery from the disease once injected with the IL4-expressing HD-Ad vector. The therapeutic effect is due to the ability of IL4 to increase, in inflamed CNS areas, chemokines (CCL1, CCL17 and CCL22) capable of recruiting regulatory T cells (CD4+CD69−CD25+Foxp3+) with suppressant functions. CSF delivery of HD-Ad vectors expressing anti-inflammatory molecules might represent a valuable therapeutic option for CNS inflammatory disorders.

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Acknowledgements

This work was supported by grants from the Italian Multiple Sclerosis Foundation (FISM), the Myelin Project, the Cariplo Foundation and the Italian Ministry of Education and Scientific Research (MIUR-FIRB). We acknowledge the technical help of V Lampasona, C Porcheri and L Muzio.

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Author notes

  1. G Martino and R Furlan: These authors contributed equally to this work.

Authors and Affiliations

  1. Neuroimmunology Unit, San Raffaele Scientific Institute, Milan, Italy

    E Butti, A Bergami, E Brambilla, A Cattalini, M Esposito, S Pluchino, G Martino & R Furlan

  2. Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy

    A Recchia & F Mavilio

  3. Neurological Department, San Raffaele Scientific Institute, Milan, Italy

    U Del Carro, S Amadio, G Comi, G Martino & R Furlan

  4. Molmed s.p.a., Milan, Italy

    A Stornaiuolo

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  1. E Butti
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Correspondence to R Furlan.

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Supplementary Information accompanies the paper on Gene Therapy website (http://www.nature.com/gt)

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Butti, E., Bergami, A., Recchia, A. et al. IL4 gene delivery to the CNS recruits regulatory T cells and induces clinical recovery in mouse models of multiple sclerosis. Gene Ther 15, 504–515 (2008). https://doi.org/10.1038/gt.2008.10

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  • DOI: https://doi.org/10.1038/gt.2008.10

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