title: Use of cytokine immunotherapy to block CNS demyelination induced by a recombinant HSV-1 expressing IL-2.
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.
authors.affiliation: Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery and Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Zandian
authors.forename: K R
authors.initials: KR
authors.lastname: Mott
authors.forename: S J
authors.initials: SJ
authors.lastname: Allen
authors.forename: O
authors.initials: O
authors.lastname: Dumitrascu
authors.forename: J Z
authors.initials: JZ
authors.lastname: Kuo
authors.forename: H
authors.initials: H
authors.lastname: Ghiasi
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000473:pathology; D016207:Cytokines / Q000235:genetics*; D003711:Demyelinating Diseases / Q000517:prevention & control*; D005260:Female; D005822:Genetic Vectors; D018259:Herpesvirus 1, Human / Q000235:genetics*; D007167:Immunotherapy; D018664:Interleukin-12 / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics; D007378:Interleukins / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL
chemical_list: D016207:Cytokines; D007376:Interleukin-2; D007378:Interleukins; C532417:interleukin-35, human; D018664:Interleukin-12