Autoimmunity and Anti-TNF-α Agents

Atzeni, Fabiola; Turiel, M.; Capsoni, F.; Doria, Andrea; Meroni, Pier Luigi; Sarzi-Puttini, Piercarlo

doi:10.1196/annals.1361.100

Cited by 148 publications

(97 citation statements)

References 51 publications

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“…While treatment of RA patients with TNFα blockade is associated with a reduction in the levels of specific autoantibodies, such as rheumatoid factor (RF), and anticyclic citrunillated peptides, it has also been associated with the induction of non-organ specific autoantibodies, such as antinuclear Abs (ANA), anti-dsDNA, and antiphospholipid Abs (aPL) [74,75].…”

Section: Mechanism Of Treatment-limiting Adverse Responsesmentioning

confidence: 99%

TNFα blockade in human diseases: Mechanisms and future directions

Wong

Ziring

Korin

et al. 2008

Clinical Immunology

260

162

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Tumor necrosis factor-alpha (TNFα) antagonists have shown remarkable efficacy in a variety of immune-mediated inflammatory diseases (IMIDs). Therapeutic scope and limitations of these agents are reviewed in a recently published article in the Journal. In spite of their therapeutic popularity, little is known about their modes of action in vivo and factors that limit their scope of therapeutic use. Intriguingly, while all TNFα antagonists including blocking antibodies and soluble receptors are effective in certain IMIDs, only anti-TNFα antibodies are effective in other IMIDs. Early efforts at understanding how TNFα antagonists act in IMIDs centered on their ability to neutralize soluble TNFα or to block TNF receptors from binding to their ligands. Subsequent studies suggested a role of complement-mediated lysis or antibody-dependent cell cytotoxicity in their therapeutic effects. More recent models postulate that TNFα blockers may act by affecting intracellular signaling, with the end result being a hastened cell cycle arrest, apoptosis, suppression of cytokine production, or improved Treg cell function. TNFα antagonists can also modulate the functions of myofibroblasts and osteoclasts, which might explain how TNFα antagonists reduce tissue damage in chronic IMIDs. Focusing on the human therapeutic experience, this analytical review will review the biology of mechanisms of action, the limiting factors contributing to disease restriction in therapeutic efficacy, and the mechanism and frequency of treatment-limiting adverse responses of TNFα antagonists. It is hoped that the overview will address the needs of clinicians to decide on optimal use, spur clinical innovation, and incite translational researchers to set priorities for in vivo human investigations.

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Section: Mechanism Of Treatment-limiting Adverse Responsesmentioning

confidence: 99%

TNFα blockade in human diseases: Mechanisms and future directions

Wong

Ziring

Korin

et al. 2008

Clinical Immunology

260

162

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“…Anti-TNF-a therapy is now in widespread use for rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, and new indications for its use are emerging including sarcoidosis and inflammatory eye disease. 87,[121][122][123] In the eye, these agents are variably efficacious in inflammatory diseases including uveitis, scleritis, and OID. There are three currently available agents in this class, two of which are monoclonal antibodies, infliximab and adalimumab, and one is a soluble TNF receptor fusion protein, etanercept.…”

Section: Therapeutic Interventionmentioning

confidence: 99%

Orbital inflammatory disease: a diagnostic and therapeutic challenge

Gordon

2006

Eye

176

115

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“…TNF-␣ is a multifunctional cytokine that plays a key role in inflammation, autoimmunity, and antitumor reaction, and mediates the response to infection (13)(14)(15). ADAM17/TACE is the primary sheddase responsible for pro-TNF-␣ cleavage in T cells or myeloid cells.…”

mentioning

confidence: 99%

Tetraspanins Regulate ADAM10-Mediated Cleavage of TNF-α and Epidermal Growth Factor

Arduise

Abache

et al. 2008

The Journal of Immunology

128

105

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Several cytokines and growth factors are released by proteolytic cleavage of a membrane-anchored precursor, through the action of ADAM (a disintegrin and metalloprotease) metalloproteases. The activity of these proteases is regulated through largely unknown mechanisms. In this study we show that Ab engagement of several tetraspanins (CD9, CD81, CD82) increases epidermal growth factor and/or TNF-α secretion through a mechanism dependent on ADAM10. The effect of anti-tetraspanin mAb on TNF-α release is rapid, not relayed by intercellular signaling, and depends on an intact MEK/Erk1/2 pathway. It is also associated with a concentration of ADAM10 in tetraspanin-containing patches. We also show that a large fraction of ADAM10 associates with several tetraspanins, indicating that ADAM10 is a component of the “tetraspanin web.” These data show that tetraspanins regulate the activity of ADAM10 toward several substrates, and illustrate how membrane compartmentalization by tetraspanins can control the function of cell surface proteins such as ectoproteases.

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Autoimmunity and Anti-TNF-α Agents

Cited by 148 publications

References 51 publications

TNFα blockade in human diseases: Mechanisms and future directions

TNFα blockade in human diseases: Mechanisms and future directions

Orbital inflammatory disease: a diagnostic and therapeutic challenge

Tetraspanins Regulate ADAM10-Mediated Cleavage of TNF-α and Epidermal Growth Factor

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