Multiple sclerosis (MS) is an inflammatory disease of the central nerv
ous system (CNS) characterized by localized areas of demyelination(1).
Although the etiology and pathogenesis of MS remain largely unknown,
it is generally assumed that immune responses to myelin antigens contr
ibute to the disease process(1,2). The exact sequence of events, as we
ll as the molecular mediators that lead to myelin destruction, is yet
to be defined(2,3) As a potent mediator of inflammation, the cytopathi
c cytokine, tumor necrosis factor (TNF) has been considered to be a st
rong candidate in the pathogenesis of MS and its animal model, experim
ental autoimmune encephalomyelitis (EAE)(3-5). However, its role in im
mune-mediated demyelination remains to be elucidated. To determine the
contribution of TNF to the pathogenesis of the MS-like disease provok
ed by the myelin oligodendrocyte glycoprotein (MOG)(6), we have tested
mice with an homologous disruption of the gene encoding TNF (ref. 7).
Here we report that upon immunization with MOG, mice lacking TNF deve
lop severe neurological impairment with high mortality and extensive i
nflammation and demyelination. We show further that inactivation of th
e TNF gene converts MOG-resistant mice to a state of high susceptibili
ty. Furthermore, treatment with TNF dramatically reduces disease sever
ity in both TNF-/- mice and in other TNF+/+ mice highly susceptible to
the MOG-induced disease. These findings indicate that TNF is not esse
ntial for the induction and expression of inflammatory and demyelinati
ng lesions, and that it may limit the extent and duration of severe CN
S pathology.