TNF-α in asthma

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Although only 5–10% of patients with asthma are relatively unresponsive to treatment with inhaled corticosteroids, refractory asthma represents an important condition, as these patients suffer considerable morbidity and mortality and consume a disproportionately large amount of health resource. Treatment options are limited and there is a large unmet clinical need for additional therapies. Tumour necrosis factor (TNF)-α is a pro-inflammatory cytokine that has been implicated in many aspects of the airway pathology in asthma, and which has recently been highlighted as potentially important in refractory asthma. The development of neutralising biological agents against TNF-α has allowed us to test the role of this cytokine in vivo. Preliminary studies have demonstrated an improvement in lung function, airway hyperresponsiveness and asthma quality-of-life, together with a reduction in exacerbation frequency, in patients treated with anti-TNF-α therapy.

Introduction

Tumour necrosis factor (TNF)-α is an important cytokine in the innate immune response, which provides immediate host defence against invading organisms before activation of the adaptive immune system [1]. It is principally produced by macrophages in response to activation of membrane-bound pattern-recognition molecules, which detect common bacterial cell surface products such as polysaccharide, carbohydrates and lipopolysaccarides. TNF-α is initially produced as a biologically active 26kDa membrane-anchored precursor protein [2], which is subsequently cleaved, principally by TNF-α-converting enzyme [3], to release the 17kDa free protein. These proteins form biologically active homotrimers [4] that act on the ubiquitously expressed TNF-α receptors 1 and 2 (p55 and p75, or TNFR1 and TNFR2) [5]. This receptor–ligand interaction causes intracellular signalling without internalisation of the complex, leading to phosphorylation of nuclear factor-κB and thus activation of the p50-p65 subunit, which then interacts with the DNA chromatin structure to increase transcription of pro-inflammatory genes such as interleukin (IL)-8, IL-6 and TNF-α itself. The response to TNF-α activation is balanced by shedding of the extracellular domain of the TNF-α receptors.

Here, we review the evidence associating TNF-α with asthma airway biology, and summarise the findings of currently published clinical trials of anti-TNF-α therapy in asthma.

Section snippets

Biological activities of TNFα in relation to asthma

Dysregulated TNF-α responses have been implicated in several inflammatory conditions. In rheumatoid arthritis — a common destructive arthropathy in which TNF-α is produced by macrophages and monocytes in response to activation by CD4+ T cells — TNF-α is measurable in increased concentration in the synovial fluid and in the serum [6]. Antagonism of TNF-α in patients with rheumatoid disease, through treatment with either recombinant soluble receptors or neutralising antibodies, leads to

Clinical trials of anti-TNF-α therapy

The current commercially available TNF-α blockers are infliximab (a chimeric mouse/human monoclonal antibody), etanercept (a soluble fusion protein combining two p75 TNF receptors with a Fc fragment of human IgG1) and adalimumab (a fully human monoclonal antibody). Clinical trials of anti-TNFα therapy in asthma are summarised in Table 1.

In an uncontrolled study of etanercept in severe (Global Initiative on Asthma [GINA] stage V) asthma, Howarth et al. [26] demonstrated a significant (2.5

Conclusions

In summary, TNF-α is a potentially important cytokine in refractory asthma, and preliminary studies on small numbers of patients have demonstrated an improvement in lung function, airway hyperresponsiveness, asthma quality-of-life and exacerbation rate following treatment with anti-TNF therapy. These findings, however, have not been consistently repeatable, and any potential role for TNF-α antagonism in refractory asthma needs to be established in a sufficiently powered large-scale clinical

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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