Tumour necrosis factor-alpha blockade suppresses murine allergic airways inflammation.
Asthma is a heterogeneous disease that has been increasing in incidence throughout western societies and cytokines, including proinflammatory tumour necrosis factor alpha (TNF-alpha), have been implicated in the pathogenesis of asthma. Anti-TNF-alpha therapies have been established successfully in the clinic for diseases such as rheumatoid arthritis and Crohn's disease. TNF-alpha-blocking strategies are now being trialled in asthma; however, their mode of action is poorly understood. Based on the observation that TNF-alpha induces lymph node hypertrophy we have attempted to investigate this as a mechanism of action of TNF-alpha in airway inflammation by employing two models of murine airway inflammation, that we have termed short and long models, representing severe and mild/moderate asthma, respectively. The models differ by their immunization schedules. In the short model, characterized by eosinophilic and neutrophilic airway inflammation the effect of TNF-alpha blockade was a reduction in draining lymph node (DLN) hypertrophy, eosinophilia, interleukin (IL)-5 production and immunoglobulin E (IgE) production. In the long model, characterized by eosinophilic inflammation, TNF-alpha blockade produced a reduction in DLN hypertrophy and IL-5 production but had limited effects on eosinophilia and IgE production. These results indicate that anti-TNF-alpha can suppress DLN hypertrophy and decrease airway inflammation. Further investigations showed that anti-TNF-alpha-induced inhibition of DLN hypertrophy cannot be explained by preventing l-selectin-dependent capture of lymphocytes into the DLN. Given that overall TNF blockade was able to suppress the short model (severe) more effectively than the long model (mild/moderate), the results suggest that TNF-alpha blocking therapies may be more effective in the treatment of severe asthma.
Hutchison
S
S
Centre for Biophotonics, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK. s.hutchison@strath.ac.uk
Choo-Kang
B S W
BS
Bundick
R V
RV
Leishman
A J
AJ
Brewer
J M
JM
McInnes
I B
IB
Garside
P
P
D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000276:immunology; D016207:Cytokines / Q000276:immunology*; D004802:Eosinophilia; D000068800:Etanercept; D005434:Flow Cytometry; D006984:Hypertrophy; D007074:Immunoglobulin G / Q000627:therapeutic use*; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D010047:Ovalbumin; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000276:immunology*; D013995:Time; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D016207:Cytokines; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D010047:Ovalbumin; D000068800:Etanercept