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HSV-1-mediated IL-1 receptor antagonist gene therapy ameliorates MOG35–55-induced experimental autoimmune encephalomyelitis in C57BL/6 mice

Gene Therapy volume 14, pages 93–98 (2007)Cite this article

Abstract

Primary proinflammatory cytokines, such as IL-1β, play a crucial pathogenic role in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE), and may represent, therefore, a suitable therapeutic target. We have previously established the delivery of anti-inflammatory cytokine genes within the central nervous system (CNS), based on intracisternal (i.c.) injection of non-replicative HSV-1-derived vectors. Here we show the therapeutic efficacy of i.c. administration of an HSV-1-derived vector carrying the interleukin-1receptor antagonist (IL-1ra) gene, the physiological antagonist of the proinflammatory cytokine IL-1, in C57BL/6 mice affected by myelin oligodendrocyte glycoprotein-induced EAE. IL-1ra gene therapy is effective preventively, delaying EAE onset by almost 1 week (22.4±1.4 days post-immunization vs 15.9±2.1 days in control mice; P=0.0229 log-rank test), and decreasing disease severity. Amelioration of EAE course was associated with a reduced number of macrophages infiltrating the CNS and in a decreased level of proinflammatory cytokine mRNA in the CNS, suggesting an inhibitory activity of IL-1ra on effector cell recruitment, as antigen-specific peripheral T-cell activation and T-cell recruitment to the CNS is unaffected. Thus, local IL-1ra gene therapy may represent a therapeutic alternative for the inhibition of immune-mediated demyelination of the CNS.

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Acknowledgements

This work has been supported by the Italian Foundation for Multiple Sclerosis (FISM), the Italian Ministry of Health and the Italian Ministry of Education, University and Research (MIUR).

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Authors and Affiliations

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

    R Furlan, A Bergami, E Brambilla, E Butti, M Campagnoli & G Martino

  2. Department of Neurology, San Raffaele Scientific Institute, Milan, Italy

    R Furlan, G Comi & G Martino

  3. Department of Neuroscience, Laboratory of Inflammation and Nervous System Diseases, Mario Negri Institute for Pharmacological Research, Milano, Italy

    M G De Simoni

  4. Department of Experimental and Diagnostic Medicine, Section of Microbiology, University of Ferrara, Ferrara, Italy

    P Marconi

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  1. R Furlan
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  2. A Bergami
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  3. E Brambilla
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  4. E Butti
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  7. P Marconi
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  8. G Comi
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  9. G Martino
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Correspondence to R Furlan.

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Furlan, R., Bergami, A., Brambilla, E. et al. HSV-1-mediated IL-1 receptor antagonist gene therapy ameliorates MOG35–55-induced experimental autoimmune encephalomyelitis in C57BL/6 mice. Gene Ther 14, 93–98 (2007). https://doi.org/10.1038/sj.gt.3302805

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