TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination.
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by localized areas of demyelination. Although the etiology and pathogenesis of MS remain largely unknown, it is generally assumed that immune responses to myelin antigens contribute to the disease process. The exact sequence of events, as well as the molecular mediators that lead to myelin destruction, is yet to be defined. As a potent mediator of inflammation, the cytopathic cytokine, tumor necrosis factor (TNF) has been considered to be a strong candidate in the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE). However, its role in immune-mediated demyelination remains to be elucidated. To determine the contribution of TNF to the pathogenesis of the MS-like disease provoked by the myelin oligodendrocyte glycoprotein (MOG), we have tested mice with an homologous disruption of the gene encoding TNF. Here we report that upon immunization with MOG, mice lacking TNF develop severe neurological impairment with high mortality and extensive inflammation and demyelination. We show further that inactivation of the TNF gene converts MOG-resistant mice to a state of high susceptibility. Furthermore, treatment with TNF dramatically reduces disease severity in both TNF-/- mice and in other TNF+/+ mice highly susceptible to the MOG-induced disease. These findings indicate that TNF is not essential for the induction and expression of inflammatory and demyelinating lesions, and that it may limit the extent and duration of severe CNS pathology.
Liu
J
J
Neuroimmunology Laboratory, La Trobe University, Bundoora, Melbourne, Australia.
Marino
M W
MW
Wong
G
G
Grail
D
D
Dunn
A
A
Bettadapura
J
J
Slavin
A J
AJ
Old
L
L
Bernard
C C
CC
D000818:Animals; D003433:Crosses, Genetic; D005260:Female; D006579:Heterozygote; D007249:Inflammation; D008214:Lymphocytes / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D009185:Myelin Proteins; D009186:Myelin Sheath / Q000473:pathology; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D009836:Oligodendroglia / Q000502:physiology; D011994:Recombinant Proteins / Q000627:therapeutic use; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency* / Q000502:physiology* / Q000627:therapeutic use
C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha