Anti-TNF-α Agents in the Treatment of Immune-mediated Inflammatory Diseases: Mechanisms of Action and Pitfalls

Léia CR Silva; Luciena CM Ortigosa; Gil Benard

Disclosures

Immunotherapy. 2010;2(6):817-833. 

In This Article

Abstract and Introduction

Abstract

TNF-α is a potent inducer of the inflammatory response, a key regulator of innate immunity and plays an important role in the regulation of Th1 immune responses against intracellular bacteria and certain viral infections. However, dysregulated TNF can also contribute to numerous pathological situations. These include immune-mediated inflammatory diseases (IMIDs) including rheumatoid arthritis, Crohn's disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis and severe chronic plaque psoriasis. Animal and human studies concerning the role of TNF-α in IMIDs have led to the development of a therapy based on TNF blockage. This article focuses first on the potential mechanisms by which the three currently licensed agents, adalimumab, etarnecept and infliximab, decrease the inflammatory activity of patients with different IMIDs. Second, it focuses on the risks, precautions and complications of the use of TNF-α inhibitors in these patients.

Introduction

TNF-α was first described by Lloyd Old et al. in 1975 as an endotoxin-induced glycoprotein, which caused hemorrhagic necrosis of solid tumors.[1] TNF-α is released as a soluble cytokine (sTNF, a homotrimer of 17 kDa monomers) after being enzymatically cleaved from its cell-surface-bound precursor (transmembrane TNF [tmTNF], a homotrimer of 26 kDa monomers) by TNF-α-converting enzyme. Both sTNF and tmTNF are biologically active. TNF is produced by numerous cell types, including immune cells (B cells and T cells, basophils, eosinophils, dendritic cells, natural killer cells, neutrophils and mast cells), nonimmune cells (astrocytes, fibroblasts, glial cells, granuloma cells and keratinocytes) and many kinds of tumor cells.[2]

The biological activity of TNF-α is triggered by binding to one of two structurally distinct receptors: TNF receptor type I (TNFRI [or p55 or CD120a]) and TNF receptor type II (TNFRII [or p75 or CD120b]). TNFRI and TNFRII are present in all cell types except erythrocytes. TNF-α is a potent inducer of the inflammatory response, a key regulator of innate immunity, and plays an important role in the regulation of Th1 immune responses against intracellular bacteria and certain viral infections.[3,4] However, dysregulated TNF can also contribute to numerous pathological situations. These include immune-mediated inflammatory diseases (IMIDs) such as rheumatoid arthritis (RA), Crohn's disease (CD), psoriatic arthritis (PsA), ankylosing spondylitis (AS), ulcerative colitis and severe chronic plaque psoriasis.

Both animal and human studies concerning the role of TNF-α in IMIDs have led to the development of therapy based on TNF blockage. Three drugs, Remicade® (infliximab; Centocor Ortho Biotech, PA, USA), Enbrel® (etanercept; Immunex, CA, USA) and Humira® (adalimumab; Abbott, IL, USA) are currently licensed as TNF-blocking agents. Although these drugs have shown efficacy in the treatment of IMIDs, the precise mechanisms of action of TNF-blocking agents remain unresolved. In this article, the possible mechanisms involved in the efficacy of treatment using TNF-blocking agents are discussed.

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