Elsevier

Autoimmunity Reviews

Volume 2, Issue 6, October 2003, Pages 346-357
Autoimmunity Reviews

The biology of TNF blockade

https://doi.org/10.1016/S1568-9972(03)00048-XGet rights and content

Abstract

Rheumatoid arthritis and Crohn's disease are costly diseases that result in significant long-term patient disability. They are chronic inflammatory diseases that are associated with increased production of Tumor Necrosis Factor (TNF). Blockage of this cytokine with bio-engineered compounds has significantly changed therapy of these diseases and has ushered in the era of biological therapy. The pro-inflammatory role of TNF is mediated by its essential respiratory burst function that is effectively inhibited by anti-TNF therapy. Anti-TNF therapy is effective in approximately two-thirds of patients to whom it is administered, but the effect is temporary. Lack of response to anti-TNF therapy stems from interplay of host-factors including: host cytokine response, disease phenotype, and antibody response to the anti-TNF agents. NOD 2, a defect present in approximately 50% of Crohn's disease patients, bears no relationship to non-response. Additionally, TNF promoter gene polymorphisms and TNF receptor gene heterogeneity play a significant role in non-response and disease course/severity. Adverse effects of anti-TNF therapy include early and delayed hypersensitivity reactions, cell-mediated infections, lupus-like syndrome, demyelinating diseases, and exacerbation of CHF.

Introduction

The process of TNF production starts with the binding of a ligand (which is commonly a microbial product) to a cell surface Toll receptor, which stimulates a signal transduction pathway that activates NFkB transcription factors. Epithelial cells, macrophages, and dendritic cells are integral participants in innate defense and therefore have a higher proportion of receptors for ligand binding. Activated NFkB enters nuclei and induces the transcription of genes associated with inflammation, including those coding for TNF. The production of TNF and other inflammatory cytokines serves to recruit other inflammatory cells, which in turn release cytokines and subsequently amplify the immune response. TNF exerts its effect via binding of TNFR1 and TNFR2 receptors. Receptor binding induces apoptosis, c-Jun N-terminal kinase/stress activated protein kinase (JNK/SAPK) or NFkB activation. Heterogeneity in the response results from the variable expression of NFkB transcription factors in a cell and tissue-specific pattern.

TNF is a versatile cytokine that alters tissue remodeling, epithelial cell barrier permeability, activation of macrophages, and recruitment of inflammatory infiltrate and up-regulation of adhesion molecules. It also plays a fundamental role in the development, homeostasis and adaptive responses of the immune system. In response to signals, which include microbial products and cytokines such as TNF, dendritic cells (DCs) mature and change their surface pattern, upgrade co- stimulatory molecules, down-regulate antigen acquisition pathways and migrate in order to recruit other inflammatory cells. The maturation and activation of DCs induces a TH1 cytokine response. Additionally, activation of NFkB after cell receptor binding upregulates anti-apoptotic genes, and these genes inhibit apoptosis of T and B cells. This promotes survival of these inflammatory cells and engenders a more sustained inflammatory response.

Multiple mechanisms for down regulating cellular uptake of bound antigens have been identified. These complex mechanisms involve transcription factors, which encode genes that inhibit antigen uptake and promote production of cytokines. The Nuclear factors of activated cells (NFAT) family are transcription factors that bind cooperatively with AP-1 promoters to the IL-2 promoter or other promoters depending on the isoform. The NFATc·Beta isoform binds and transactivates the TNF alpha promoter. Indeed, studies of deletion mutations as well as mutants swapping the C terminal region of the DNA binding domain reveal that different NFAT proteins may program the temporal expression of distinct cytokine genes.

Section snippets

Responders

Anti-TNF therapy has been shown to have good efficacy for the treatment of Crohn's disease and rheumatoid arthritis. The efficacy of anti-TNF therapy has been validated by short and long-term phase III studies [1], [2]. In Crohn's disease, infliximab, an IgG1 murine-human chimeric antibody, has been shown to be effective. However, etanercept, a fusion protein of recombinant human TNF-receptor and human IgG1, has not been proven to be effective despite preliminary results that were promising [3]

Non-responders

Significant clinical response to anti-TNF therapy occurs within 2–4 weeks of a single treatment. Little response occurs after 6 weeks. The duration of response is variable. Some correspondence of response duration to the serum level of anti-TNF antibody has been established. These antibodies may be detected up to 13 weeks post infusion. Usually, the results of prior infusions are duplicated after subsequent infusions.

Some patients do not respond to biological therapy while others have a

Notable complications of anti TNF therapy

The potential for development of adverse events with anti-TNF agents serves as an unfortunate limitation to this therapy. Though many clinical and therapeutic trials have established a myriad of possible adverse events, estimation of their frequency is only reflective of a limited observation period. Anti-TNF therapy can potentially elicit a variety of side effects, which can be broadly categorized as infusion reactions specific to infliximab, hypersensitivity reactions, various infections,

Further reading

Van Dullemen HM, Van Deventer S, Hommes DW, Bijl HA, Jansen J, Tytgat G, Woody J. Treatment of Crohn's Disease with Anti-Tumor Necrosis Factor Chimeric Monoclonal Antibody (cA2). Gastroenterology 1995;109:129–135.

Rutgeerts P, Van Assche G, Van Deventer S, Bao W, Keenan G, Olson A, Hanauer S, Colombel JF. Infliximab Maintenance Treatment Strategy Results in Mucosal Healing in Patients with Crohn's Disease. Digestive Disease Week; San Francisco, CA 2002; abstract W1367.

Kavanaugh

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    Van Dullemen HM, Van Deventer S, Hommes DW, Bijl HA, Jansen J, Tytgat G, Woody J. Treatment of Crohn's Disease with Anti-Tumor Necrosis Factor Chimeric Monoclonal Antibody (cA2). Gastroenterology 1995;109:129–135.

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    Kavanaugh AF, Cush JJ, St. Clair EW, McCune WJ, Braakman TAJ, Nichols LA, Lipsky PE. Ant-TNF-α Monoclonal Antibody (mAb) Treatment of Rheumatoid Arthritis (RA) Patients with Active Disease on Methotrexate (MTX); Results of A Double-Blind, Placebo Controlled Multicenter Trial. Arthritis and Rheumatism 1996;39(suppl):S123.

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