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Use of cytokine immunotherapy to block CNS demyelination induced by a recombinant HSV-1 expressing IL-2

Gene Therapy volume 18, pages 734–742 (2011)Cite this article

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Abstract

We previously have described a model of multiple sclerosis (MS) in which constitutive expression of murine interleukin (IL)-2 by herpes simplex virus type 1 (HSV-1) (HSV-IL-2) causes central nervous system (CNS) demyelination in different strains of mice. In the current study, we investigated whether this HSV-IL-2-induced demyelination can be blocked using recombinant viruses expressing different cytokines or by injection of plasmid DNA. We have found that coinfection of HSV-IL-2-infected mice with recombinant viruses expressing IL-12p35, IL-12p40 or IL-12p35+IL-12p40 did not block the CNS demyelination, and that coinfection with a recombinant virus expressing interferon (IFN)-γ exacerbated it. In contrast, coinfection with a recombinant virus expressing IL-4 reduced demyelination, whereas coinfection of HSV-IL-2-infected mice with a recombinant HSV-1 expressing the IL-12 heterodimer (HSV-IL-12p70) blocked the CNS demyelination in a dose-dependent manner. Similarly, injection of IL-12p70 DNA blocked HSV-IL-2-induced CNS demyelination in a dose-dependent manner and injection of IL-35 DNA significantly reduced CNS demyelination. Injection of mice with IL-12p35 DNA, IL-12p40 DNA, IL-12p35+IL-12p40 DNA or IL-23 DNA did not have any effect on HSV-IL-2-induced demyelination, whereas injection of IL-27 DNA increased the severity of the CNS demyelination in the HSV-IL-2-infected mice. This study demonstrates for the first time that IL-12p70 can block HSV-IL-2-induced CNS demyelination and that IL-35 can also reduce this demyelination, whereas IFN-γ and IL-27 exacerbated the demyelination in the CNS of the HSV-IL-2-infected mice. Our results suggest a potential role for IL-12p70 and IL-35 signaling in the inhibition of HSV-IL-2-induced immunopathology by preventing development of autoaggressive T cells.

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Acknowledgements

This work was supported by Public Health Service grant EY15557 from the National Eye Institute. We thank Dr James M Markert Division of Neurosurgery, Department of Surgery, University of Alabama at Birmingham for providing the M002 (HSV-IL-12p70) virus.

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Authors and Affiliations

  1. Department of Surgery and Regenerative Medicine Institute, Center for Neurobiology and Vaccine Development, Ophthalmology Research, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    M Zandian, K R Mott, S J Allen, O Dumitrascu & H Ghiasi

  2. Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    O Dumitrascu & J Z Kuo

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  1. M Zandian
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Correspondence to H Ghiasi.

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Zandian, M., Mott, K., Allen, S. et al. Use of cytokine immunotherapy to block CNS demyelination induced by a recombinant HSV-1 expressing IL-2. Gene Ther 18, 734–742 (2011). https://doi.org/10.1038/gt.2011.32

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