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, Oct 10, 2015
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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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    ABSTRACT: THE REGULATORY CYTOKINE TUMOR NECROSIS FACTOR (TNF) EXERTS ITS EFFECTS THROUGH TWO RECEPTORS: TNFR1 and TNFR2. Defects in TNFR2 signaling are evident in a variety of autoimmune diseases. One new treatment strategy for autoimmune disease is selective destruction of autoreactive T cells by administration of TNF, TNF inducers, or TNFR2 agonism. A related strategy is to rely on TNFR2 agonism to induce T-regulatory cells (Tregs) that suppress cytotoxic T cells. Targeting TNFR2 as a treatment strategy is likely superior to TNFR1 because of its more limited cellular distribution on T cells, subsets of neurons, and a few other cell types, whereas TNFR1 is expressed throughout the body. This review focuses on TNFR2 expression, structure, and signaling; TNFR2 signaling in autoimmune disease; treatment strategies targeting TNFR2 in autoimmunity; and the potential for TNFR2 to facilitate end organ regeneration.
    Frontiers in Immunology 12/2013; 4:478. DOI:10.3389/fimmu.2013.00478
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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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    ABSTRACT: No targeted immunotherapies reverse type 1 diabetes in humans. However, in a rodent model of type 1 diabetes, Bacillus Calmette-Guerin (BCG) reverses disease by restoring insulin secretion. Specifically, it stimulates innate immunity by inducing the host to produce tumor necrosis factor (TNF), which, in turn, kills disease-causing autoimmune cells and restores pancreatic beta-cell function through regeneration. Translating these findings to humans, we administered BCG, a generic vaccine, in a proof-of-principle, double-blind, placebo-controlled trial of adults with long-term type 1 diabetes (mean: 15.3 years) at one clinical center in North America. Six subjects were randomly assigned to BCG or placebo and compared to self, healthy paired controls (n = 6) or reference subjects with (n = 57) or without (n = 16) type 1 diabetes, depending upon the outcome measure. We monitored weekly blood samples for 20 weeks for insulin-autoreactive T cells, regulatory T cells (Tregs), glutamic acid decarboxylase (GAD) and other autoantibodies, and C-peptide, a marker of insulin secretion. BCG-treated patients and one placebo-treated patient who, after enrollment, unexpectedly developed acute Epstein-Barr virus infection, a known TNF inducer, exclusively showed increases in dead insulin-autoreactive T cells and induction of Tregs. C-peptide levels (pmol/L) significantly rose transiently in two BCG-treated subjects (means: 3.49 pmol/L [95% CI 2.95-3.8], 2.57 [95% CI 1.65-3.49]) and the EBV-infected subject (3.16 [95% CI 2.54-3.69]) vs.1.65 [95% CI 1.55-3.2] in reference diabetic subjects. BCG-treated subjects each had more than 50% of their C-peptide values above the 95(th) percentile of the reference subjects. The EBV-infected subject had 18% of C-peptide values above this level. We conclude that BCG treatment or EBV infection transiently modified the autoimmunity that underlies type 1 diabetes by stimulating the host innate immune response. This suggests that BCG or other stimulators of host innate immunity may have value in the treatment of long-term diabetes. NCT00607230.
    PLoS ONE 08/2012; 7(8):e41756. DOI:10.1371/journal.pone.0041756 · 3.23 Impact Factor
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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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    ABSTRACT: Non-obese diabetic (NOD) mice develop Sjögren's-like disease (SS-like) with loss of saliva flow and increased lymphocytic infiltrates in salivary glands (SGs). There are recent reports using multipotent mesenchymal stromal cells (MSCs) as a therapeutic strategy for autoimmune diseases due to their anti-inflammatory and immunomodulatory capabilities. This paper proposed a combined immuno- and cell-based therapy consisting of: A) an injection of complete Freund's adjuvant (CFA) to eradicate autoreactive T lymphocytes, and B) transplantations of MSCs to reselect lymphocytes. The objective of this was to test the effectiveness of CD45(-)/TER119(-) cells (MSCs) in re-establishing salivary function and in reducing the number of lymphocytic infiltrates (foci) in SGs. The second objective was to study if the mechanisms underlying a decrease in inflammation (focus score) was due to CFA, MSCs, or CFA+MSCs combined. Donor MSCs were isolated from bones of male transgenic eGFP mice. Eight week-old female NOD mice received one of the following treatments: insulin, CFA, MSC, or CFA+MSC (combined therapy). Mice were followed for 14 weeks post-therapy. CD45(-)/TER119(-) cells demonstrated characteristics of MSCs as they were positive for Sca-1, CD106, CD105, CD73, CD29, CD44, negative for CD45, TER119, CD11b, had high number of CFU-F, and differentiated into osteocytes, chondrocytes and adipocytes. Both MSC and MSC+CFA groups prevented loss of saliva flow and reduced lymphocytic infiltrations in SGs. Moreover, the influx of T and B cells decreased in all foci in MSC and MSC+CFA groups, while the frequency of Foxp3(+) (T(reg)) cell was increased. MSC-therapy alone reduced inflammation (TNF-α, TGF-β), but the combination of MSC+CFA reduced inflammation and increased the regenerative potential of SGs (FGF-2, EGF). The combined use of MSC+CFA was effective in both preventing saliva secretion loss and reducing lymphocytic influx in salivary glands.
    PLoS ONE 06/2012; 7(6):e38615. DOI:10.1371/journal.pone.0038615 · 3.23 Impact Factor
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