Tumour necrosis factor (TNFα) as a novel therapeutic target in symptomatic corticosteroid dependent asthma
- P H Howarth1,
- K S Babu1,
- H S Arshad1,
- L Lau1,
- M Buckley1,
- W McConnell1,
- P Beckett1,
- M Al Ali1,
- A Chauhan2,
- S J Wilson1,
- A Reynolds3,
- D E Davies1,
- S T Holgate1
- 1Allergy and Inflammation Research, Division of Infection, Inflammation and Repair, School of Medicine, Southampton General Hospital, Southampton, UK
- 2St Mary’s Hospital, Respiratory Medicine, Portsmouth, UK
- 3Wyeth Laboratories, Taplow, Maidenhead, Berkshire, UK
- Correspondence to:
Professor S T Holgate
Infection, Inflammation and Repair Division, F Level South Block (810), Southampton General Hospital, Southampton SO16 6YD, UK;
- Received 19 April 2005
- Accepted 4 August 2005
- Published Online First 15 September 2005
Background: Tumour necrosis factor α (TNFα) is a major therapeutic target in a range of chronic inflammatory disorders characterised by a Th1 type immune response in which TNFα is generated in excess. By contrast, asthma is regarded as a Th2 type disorder, especially when associated with atopy. However, as asthma becomes more severe and chronic, it adopts additional characteristics including corticosteroid refractoriness and involvement of neutrophils suggestive of an altered inflammatory profile towards a Th1 type response, incriminating cytokines such as TNFα.
Methods: TNFα levels in bronchoalveolar lavage (BAL) fluid of 26 healthy controls, 42 subjects with mild asthma and 20 with severe asthma were measured by immunoassay, and TNFα gene expression was determined in endobronchial biopsy specimens from 14 patients with mild asthma and 14 with severe asthma. The cellular localisation of TNFα was assessed by immunohistochemistry. An open label uncontrolled clinical study was then undertaken in 17 subjects with severe asthma to evaluate the effect of 12 weeks of treatment with the soluble TNFα receptor-IgG1Fc fusion protein, etanercept.
Results: TNFα levels in BAL fluid, TNFα gene expression and TNFα immunoreative cells were increased in subjects with severe corticosteroid dependent asthma. Etanercept treatment was associated with improvement in asthma symptoms, lung function, and bronchial hyperresponsiveness.
Conclusions: These findings may be of clinical significance in identifying TNFα as a new therapeutic target in subjects with severe asthma. The effects of anti-TNF treatment now require confirmation in placebo controlled studies.
- BHR, bronchial hyperresponsiveness
- FEV1, forced expiratory volume in 1 second
- FVC, forced vital capacity
- PEF, peak expiratory flow
- TNFα, tumour necrosis factor α
Published Online First 15 September 2005
This work was supported by the Medical Research Council (UK) and an educational grant from Immunex (Amgen).
Competing interests: The proof of principle trial with etanercept was an investigator initiated study that was designed, executed, and analysed without input from any pharmaceutical company. Immunex (Amgen) provided an educational grant that contributed to the costs and Wyeth provided the etanercept without charge. The authors have no other competing interests to declare.
PHH and KSB contributed equally to this work.