The therapeutic potential of tumor necrosis factor for autoimmune disease: a mechanistically based hypothesis.
Excess levels of tumor necrosis factor-alpha (TNF-alpha) have been associated with certain autoimmune diseases. Under the rationale that elevated TNF-alpha levels are deleterious, several anti-TNF-alpha therapies are now available to block the action of TNF-alpha in patients with autoimmune diseases with a chronic inflammatory component to the destructive process. TNF-alpha antagonists have provided clinical benefit to many patients, but their use also is accompanied by new or aggravated forms of autoimmunity. Here we propose a mechanistically based hypothesis for the adverse events observed with TNF-alpha antagonists, and argue for the opposite therapeutic strategy: to boost or restore TNF-alpha activity as a treatment for some forms of autoimmunity. Activation defects in the transcription factor nuclear factor kappaB leave autoreactive T cells sensitive to TNF-alpha-induced apoptosis. Treatment with TNF-alpha, by destroying autoreactive T cells, appears to be a highly targeted strategy to interrupt the pathogenesis of type 1 diabetes, lupus and certain forms of autoimmunity.
Kodama
S
S
Harvard Medical School and Massachusetts General Hospital-East, Boston, 02192, USA.
Davis
M
M
Faustman
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DL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001327:Autoimmune Diseases / Q000139:chemically induced* / Q000188:drug therapy* / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000276:immunology; D004789:Enzyme Activation; D006801:Humans; D008177:Lupus Vulgaris / Q000188:drug therapy / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016328:NF-kappa B / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha