The biology of TNF blockade
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
References (40)
- et al.
Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial
Lancet
(2002) - et al.
Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group
Lancet
(1999) - et al.
Etanercept in the treatment of active refractory Crohn's disease: a single-center pilot trial
Am J Gastroenterol
(2001) - et al.
Etanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial
Gastroenterology
(2001) - et al.
Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis
Lancet
(1994) - et al.
Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease
Gastroenterology
(1999) - et al.
ANCA pattern and LTA haplotype relationship to clinical responses to anti-TNF antibody treatment in Crohn's disease
Gastroenterology
(2001) - et al.
Demographic and clinical parameters influencing the short-term outcome of anti-tumor necrosis factor (infliximab) treatment in Crohn's disease
Am J Gastroenterol
(2002) - et al.
Predictors of response to infliximab in patients with Crohn's disease
Gastroenterology
(2002) - et al.
Serological markers for prediction of response to anti-tumor necrosis factor treatment in Crohn's disease
Am J Gastroenterol
(2002)
A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group
N Engl J Med
Infliximab for the treatment of fistulas in patients with Crohn's disease
N Engl J Med
Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial
Ann Intern Med
A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis
N Engl J Med
A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate
N Engl J Med
Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein
N Engl J Med
Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis
Arthritis Rheum
Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist
Arthritis Rheum
Investigation of promoter polymorphisms in the tumor necrosis factor-alpha and interleukin-10 genes in liver transplant patients
Transplantation
Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial
Arthritis Rheum
Cited by (93)
Age, sex, and TNF associated differences in the gut microbiota of mice and their impact on acute TNBS colitis
2017, Experimental and Molecular PathologyHow I treat juvenile idiopathic arthritis: A state of the art review
2017, Autoimmunity ReviewsTNF-alpha inhibitor associated myelopathies: A neurological complication in patients with rheumatologic disorders
2017, Journal of the Neurological SciencesCitation Excerpt :Further clinical observations showed TNFα-I worsened demyelinating disease in patients with preexisting MS enrolled in clinical trials [6,7]. Hypotheses to explain these observations suggest that since TNFα mediates the production of both inflammatory and regulatory cytokines, the chronic inhibition of TNFα could lead to an imbalance in the cytokine profile with increase in pro-inflammatory activity which in turn could cause increased recruitment of inflammatory cells to the central nervous system (CNS) and worsening of demyelinating activity [7,14]. Other studies suggest that chronic TNFα inhibition could increase T-cell autoreactivity by decreasing T-cell apoptosis [15].
TLRs, future potential therapeutic targets for RA
2017, Autoimmunity ReviewsCitation Excerpt :In the last decade, evidence from RA specimen and preclinical models have allowed us to unravel novel endogenous ligands for TLRs and to gain insight into the mechanism by which binding of these natural ligands to their corresponding receptors promotes disease. There is no cure for RA and up to 40% of the heterogeneous RA patient population does not respond to anti-TNF therapies [141]. Circulating TH-17 cells or IL-17 levels are highly elevated subsequent to TNF blockade in the non-responder population [142,143].
Clinical significance of serum TNFα and -308 G/A promoter polymorphism in rheumatoid arthritis
2015, Egyptian RheumatologistMonitoring of adalimumab and antibodies-to-adalimumab levels in patient serum by the homogeneous mobility shift assay
2013, Journal of Pharmaceutical and Biomedical Analysis
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 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.
Study II, Abbott Laboratories. Humira (adalimumab) prescribing information 2003.
Study III, Abbott Laboratories. Humira (adalimumab) prescribing information 2003.
Study IV, Abbott Laboratories. Humira (adalimumab) prescribing information 2003.
Amgen Inc. Kineret (anakinra) prescribing information 2001.
ACCENT II trial (A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen). Unpublished multi-center data from Centecor presented at Digestive Disease Week; San Francisco, CA 2002.