The Journal of Experimental Medicine
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Published online 19 February 2001.
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© The Rockefeller University Press, 0022-1007/2001/2/427/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 4, February 19, 2001 427-434

Original Article

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



George Kassiotisa,b and George Kolliasa,b

a Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens 115-21, Greece
b Institute of Immunology, Biomedical Sciences Research Center "Alexander Fleming," Vari 166-72, Greece
Institute of Immunology, Biomedical Sciences Research Center "Al. Fleming," Vari 166-72, Greece.301-9656563301-9656507

kollias{at}hol.gr

Multiple sclerosis (MS) is a disabling inflammatory demyelinating disease of 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 effects, TNF exhibits potent immunosuppressive properties, providing one possible explanation for the immune and disease activating effect of anti-TNF treatment of MS. We show that in TNF-deficient mice, myelin-specific T cell reactivity fails to regress and expansion of activated/memory T cells is abnormally prolonged, leading to exacerbated EAE. Strikingly, immnosuppression by TNF and protection against EAE does not require the p55 TNFR, whereas the 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 activities of TNF without compromising its immunosuppressive properties.

Key Words: autoimmunity • cytokines • encephalomyelitis/multiple sclerosis • T lymphocytes • transgenic/knockout

Abbreviations used in this paper: CNS, central nervous system; EAE, experimental autoimmune encephalomyelitis; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; MS, multiple sclerosis; PTx, pertussis toxin.

© 2001 The Rockefeller University Press


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