title: A herpes simplex virus-derived replicative vector expressing LIF limits experimental demyelinating disease and modulates autoimmunity.
abstract: Herpes simplex virus type 1 (HSV-1) has properties that can be exploited for the development of gene therapy vectors. The neurotropism of HSV enables delivery of therapeutic genes to the nervous system. Using a bacterial artificial chromosome (BAC), we constructed an HSV-1(17(+))-based replicative vector deleted of the neurovirulence gene γ134.5, and expressing leukemia inhibitory factor (LIF) as a transgene for treatment of experimental autoimmune encephalomyelitis (EAE). EAE is an inducible T-cell mediated autoimmune disease of the central nervous system (CNS) and is used as an animal model for multiple sclerosis. Demyelination and inflammation are hallmarks of both diseases. LIF is a cytokine that has the potential to limit demyelination and oligodendrocyte loss in CNS autoimmune diseases and to affect the T-cell mediated autoimmune response. In this study SJL/J mice, induced for EAE, were treated with a HSV-LIF vector intracranially and the subsequent changes in disease parameters and immune responses during the acute disease were investigated. Replicating HSV-LIF and its DNA were detected in the CNS during the acute infection, and the vector spread to the spinal cord but was non-virulent. The HSV-LIF significantly ameliorated the EAE and contributed to a higher number of oligodendrocytes in the brains when compared to untreated mice. The HSV-LIF therapy also induced favorable changes in the expression of immunoregulatory cytokines and T-cell population markers in the CNS during the acute disease. These data suggest that BAC-derived HSV vectors are suitable for gene therapy of CNS disease and can be used to test the therapeutic potential of immunomodulatory factors for treatment of EAE.
authors.affiliation: Department of Virology, University of Turku, Turku, Finland. michaela.nygardas@utu.fi
authors.forename: Michaela
authors.initials: M
authors.lastname: Nygårdas
authors.forename: Henrik
authors.initials: H
authors.lastname: Paavilainen
authors.forename: Nadine
authors.initials: N
authors.lastname: Müther
authors.forename: Claus-Henning
authors.initials: CH
authors.lastname: Nagel
authors.forename: Matias
authors.initials: M
authors.lastname: Röyttä
authors.forename: Beate
authors.initials: B
authors.lastname: Sodeik
authors.forename: Veijo
authors.initials: V
authors.lastname: Hukkanen
mesh_terms: D000818:Animals; D015551:Autoimmunity; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000628:therapy*; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D007155:Immunologic Factors / Q000096:biosynthesis* / Q000235:genetics; D056747:Immunomodulation; D053605:Leukemia Inhibitory Factor / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D009186:Myelin Sheath / Q000473:pathology; D009836:Oligodendroglia / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018139:Simplexvirus / Q000235:genetics*; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism / Q000821:virology; D014709:Vero Cells; D014779:Virus Replication
chemical_list: D016207:Cytokines; D007155:Immunologic Factors; D053605:Leukemia Inhibitory Factor; D012333:RNA, Messenger