Cellular and Molecular Life Sciences CMLS

, Volume 62, Issue 16, pp 1850-1862

First online:

The therapeutic potential of tumor necrosis factor for autoimmune disease: a mechanistically based hypothesis

  • S. KodamaAffiliated withHarvard Medical School and Massachusetts General Hospital-East
  • , M. DavisAffiliated withSchool of Public Health and Health Services, George Washington University
  • , D. L. FaustmanAffiliated withHarvard Medical School and Massachusetts General Hospital-East Email author 

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Excess levels of tumor necrosis factor-α (TNF-α) have been associated with certain autoimmune diseases. Under the rationale that elevated TNF-α levels are deleterious, several anti-TNF-α therapies are now available to block the action of TNF-α in patients with autoimmune diseases with a chronic inflammatory component to the destructive process. TNF-α 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-α antagonists, and argue for the opposite therapeutic strategy: to boost or restore TNF-α activity as a treatment for some forms of autoimmunity. Activation defects in the transcription factor nuclear factor κB leave autoreactive T cells sensitive to TNF-α-induced apoptosis. Treatment with TNF-α, 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.

Key words.

NF-κB TNF-α apoptosis autoimmunity