TNF IS A POTENT ANTIINFLAMMATORY CYTOKINE IN AUTOIMMUNE-MEDIATED DEMYELINATION

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.