Primary demyelination in transgenic mice expressing interferon-gamma.
Ever since the use of interferon-gamma to treat patients with multiple sclerosis resulted in enhanced disease, the role of IFN-gamma in demyelination has been under question. To address this issue directly, transgenic mice were generated that expressed the cDNA of murine IFN-gamma in the central nervous system by using an oligodendrocyte-specific promoter. Expression of the transgene occurred after 8 weeks of age, at which time the murine immune and central nervous systems are both fully developed. Directly associated with transgene expression, primary demyelination occurred and was accompanied by clinical abnormalities consistent with CNS disorders. Additionally, multiple hallmarks of immune-mediated CNS disease were observed including upregulation of MHC molecules, gliosis and lymphocytic infiltration. These results demonstrate a direct role for IFN-gamma as an inducer of CNS demyelination leading to disease and provide new opportunities for dissecting the mechanism of demyelination.
Horwitz
Marc S
MS
Departments of Immunology (IMM-23), 10550 North Torrey Pines Road, La Jolla, California 92037, USA.|Neuropharmacology, the Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Evans
Claire F
CF
Neuropharmacology, the Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Mcgavern
Dorian B
DB
Department of Neurology and Immunology, Mayo Clinic, 200 First Street, SW, Rochester, Minnesota 55905, USA.
Rodriguez
Moses
M
Department of Neurology and Immunology, Mayo Clinic, 200 First Street, SW, Rochester, Minnesota 55905, USA.
Oldstone
Michael B A
MBA
Neuropharmacology, the Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
D000818:Animals; D001483:Base Sequence; D002490:Central Nervous System / Q000648:ultrastructure; D017931:DNA Primers / Q000235:genetics; D003711:Demyelinating Diseases / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009103:Multiple Sclerosis / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D016133:Polymerase Chain Reaction
D017931:DNA Primers; D007371:Interferon-gamma