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

Harvard Medical School and Massachusetts General Hospital-East, Boston, 02192, USA.
Cellular and Molecular Life Sciences CMLS (Impact Factor: 5.81). 09/2005; 62(16):1850-62. DOI: 10.1007/s00018-005-5022-6
Source: PubMed


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.

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Available from: Shohta Kodama
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    • "This in turn biases autoreactive T cells to shift to the TRADD/FADD cell death signaling pathway which leads to apoptosis (Figure 1B). In other words, NFkB dysregulation makes autoreactive T cells selectively vulnerable to TNF-induced apoptosis (20). T cells, unlike B cells and other immune cells, do not constitutively express the active form of NFkB. "
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    • "At the time, the mechanisms behind BCG’s failure were not understood and specific biomarkers or knowledge of TNF action and autoimmunity were unavailable. In recent years, however, the mechanism of action underlying the therapeutic potential of BCG and TNF in autoimmune disease has been further elucidated [1], supporting the hypothesis based on animal data that BCG vaccination may be beneficial in type 1 diabetes, especially if the mechanism of action of BCG trigger TNF can be closely followed with sophisticated and early biomarkers of safety. "
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    • "The first step (immune-modifying therapy) consisted of one injection of complete Freund's adjuvant (CFA) to increase the levels of endogenous tumor necrosis factor alpha (TNFα) to eradicate autoreactive T lymphocytes through apoptosis. The second step (cell therapy) was injections/transplantation of major histocompatibility complex (MHC) class I-matched bone marrow cells from healthy mice to reselect lymphocytes [8], [10], [11]. Although saliva secretion improved in NOD mice treated by our combined immuno- and cell-based therapy, no differences were observed in focus score (number of lymphocytic infiltrates) [7]. "
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