Uncoupling the proinflammatory from the immunosuppressive properties of tumor necrosis factor (TNF) at the p55 TNF receptor level: Implications for pathogenesis and therapy of autoimmune demyelination

Multiple sclerosis (MS) is a disabling inflammatory demyelinating disease o f the central nervous system, considered to result from self-reactivity to myelin antigens. Tumor necrosis factor (TNF) and the p55 TNF receptor (TNFR ) have been strongly implicated in MS pathogenesis. We reveal in this study a dual role for TNF in experimental autoimmune encephalomyelitis (EAE), a mouse model for MS. In addition to its well-established proinflammatory eff ects, TNF exhibits potent immunosuppressive properties, providing one possi ble explanation for the immune and disease activating effect of anti-TNF tr eatment of MS. We show that in TNF-deficient mice, myelin-specific T cell r eactivity fails to regress and expansion of activated/memory T cells is abn ormally prolonged, leading to exacerbated EAE. Strikingly, immnosuppression by TNF and protection against EAE does not require the p55 TNFR, whereas t he same receptor is necessary for the detrimental effects of TNF during the acute phase of the disease. Thus, blocking the function of the p55 TNFR in autoimmune demyelination may inhibit the noxious proinflammatory activitie s of TNF without compromising its immunosuppressive properties.