title: Intrathecal delivery of IFN-gamma protects C57BL/6 mice from chronic-progressive experimental autoimmune encephalomyelitis by increasing apoptosis of central nervous system-infiltrating lymphocytes.
abstract: The exclusive detrimental role of proinflammatory cytokines in demyelinating diseases of the CNS, such as multiple sclerosis, is controversial. Here we show that the intrathecal delivery of an HSV-1-derived vector engineered with the mouse IFN-gamma gene leads to persistent (up to 4 wk) CNS production of IFN-gamma and inhibits the course of a chronic-progressive form of experimental autoimmune encephalomyelitis (EAE) induced in C57BL/6 mice by myelin oligodendrocyte glycoprotein (MOG)(35-55). Mice treated with the IFN-gamma-containing vector before EAE onset showed an earlier onset but a milder course of the disease compared with control mice treated with the empty vector. In addition, 83% of IFN-gamma-treated mice completely recovered within 25 days post immunization, whereas control mice did not recover up to 60 days post immunization. Mice treated with the IFN-gamma-containing vector within 1 wk after EAE onset partially recovered from the disease within 25 days after vector injection, whereas control mice worsened. Recovery from EAE in mice treated with IFN-gamma was associated with a significant increase of CNS-infiltrating lymphocytes undergoing apoptosis. During the recovery phase, the mRNA level of TNFR1 was also significantly increased in CNS-infiltrating cells from IFN-gamma-treated mice compared with controls. Our results further challenge the exclusive detrimental role of IFN-gamma in the CNS during EAE/multiple sclerosis, and indicate that CNS-confined inflammation may induce protective immunological countermechanisms leading to a faster clearance of encephalitogenic T cells by apoptosis, thus restoring the immune privilege of the CNS.
authors.affiliation: Neuroimmunology Unit, DIBIT, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Furlan
authors.forename: E
authors.initials: E
authors.lastname: Brambilla
authors.forename: F
authors.initials: F
authors.lastname: Ruffini
authors.forename: P L
authors.initials: PL
authors.lastname: Poliani
authors.forename: A
authors.initials: A
authors.lastname: Bergami
authors.forename: P C
authors.initials: PC
authors.lastname: Marconi
authors.forename: D M
authors.initials: DM
authors.lastname: Franciotta
authors.forename: G
authors.initials: G
authors.lastname: Penna
authors.forename: G
authors.initials: G
authors.lastname: Comi
authors.forename: L
authors.initials: L
authors.lastname: Adorini
authors.forename: G
authors.initials: G
authors.lastname: Martino
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D001812:Blood-Brain Barrier / Q000235:genetics / Q000276:immunology; D001921:Brain / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D002552:Cerebral Ventricles / Q000276:immunology / Q000821:virology; D002908:Chronic Disease; D002946:Cisterna Magna; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage; D018259:Herpesvirus 1, Human / Q000235:genetics; D007267:Injections; D007278:Injections, Spinal; D007371:Interferon-gamma / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D018655:Lymphocyte Count; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D047888:Receptors, Tumor Necrosis Factor, Type I; D013116:Spinal Cord / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013346:Subarachnoid Space / Q000276:immunology / Q000821:virology; D014779:Virus Replication / Q000235:genetics
chemical_list: D015703:Antigens, CD; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D007371:Interferon-gamma