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

doi:10.1084/jem.193.4.427

Published online 12 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 Kassiotis^a,b and George Kollias^a,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

Correspondence to: George Kollias, Institute of Immunology, Biomedical Sciences Research Center “Al. Fleming,” Vari 166-72, Greece. Tel:301-9656507 Fax:301-9656563 E-mail:kollias{at}hol.gr.

Multiple sclerosis (MS) is a disabling inflammatory demyelinatingdisease of the central nervous system, considered to resultfrom self-reactivity to myelin antigens. Tumor necrosis factor(TNF) and the p55 TNF receptor (TNFR) have been strongly implicatedin MS pathogenesis. We reveal in this study a dual role forTNF in experimental autoimmune encephalomyelitis (EAE), a mousemodel for MS. In addition to its well-established proinflammatoryeffects, TNF exhibits potent immunosuppressive properties, providingone possible explanation for the immune and disease activatingeffect of anti-TNF treatment of MS. We show that in TNF-deficientmice, myelin-specific T cell reactivity fails to regress andexpansion of activated/memory T cells is abnormally prolonged,leading to exacerbated EAE. Strikingly, immnosuppression byTNF and protection against EAE does not require the p55 TNFR,whereas the same receptor is necessary for the detrimental effectsof TNF during the acute phase of the disease. Thus, blockingthe function of the p55 TNFR in autoimmune demyelination mayinhibit the noxious proinflammatory activities of TNF withoutcompromising its immunosuppressive properties.

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

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