Tumour necrosis factor (TNFalpha) as a novel therapeutic target in symptomatic corticosteroid dependent asthma.
BACKGROUND
Tumour necrosis factor alpha (TNFalpha) is a major therapeutic target in a range of chronic inflammatory disorders characterised by a Th1 type immune response in which TNFalpha 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 TNFalpha.


METHODS
TNFalpha 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 TNFalpha gene expression was determined in endobronchial biopsy specimens from 14 patients with mild asthma and 14 with severe asthma. The cellular localisation of TNFalpha 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 TNFalpha receptor-IgG1Fc fusion protein, etanercept.


RESULTS
TNFalpha levels in BAL fluid, TNFalpha gene expression and TNFalpha 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 TNFalpha as a new therapeutic target in subjects with severe asthma. The effects of anti-TNF treatment now require confirmation in placebo controlled studies.
Howarth
P H
PH
Allergy and Inflammation Research, Division of Infection, Inflammation and Repair, School of Medicine, F Level South Block (810), Southampton General Hospital, Southampton SO16 6YD, UK.
Babu
K S
KS
Arshad
H S
HS
Lau
L
L
Buckley
M
M
McConnell
W
W
Beckett
P
P
Al Ali
M
M
Chauhan
A
A
Wilson
S J
SJ
Reynolds
A
A
Davies
D E
DE
Holgate
S T
ST
D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001249:Asthma / Q000378:metabolism* / Q000628:therapy; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry*; D001999:Bronchoscopy / Q000379:methods; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D000068800:Etanercept; D005260:Female; D005336:Fiber Optic Technology; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007074:Immunoglobulin G; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept