Trends in Immunology
A role for eosinophils in airway remodelling in asthma
Section snippets
Asthma and remodelling
The remodelled phenotype in asthma, which might be the consequence of excessive repair processes following repeated airway injury, includes increased deposition of several extracellular matrix (ECM) proteins in the reticular basement membrane (RBM) and bronchial mucosa, as well as increases in airway smooth muscle mass, goblet-cell hyperplasia and new blood vessel formation [11]. These ECM proteins include pro-collagen III (the mature precursor for collagen III) and the proteoglycans, tenascin
Role of TGF-β
TGF-β, in particular, is a potent regulator of fibroblast and myofibroblast function and controls the production of several ECM proteins, including collagens, proteoglycans and tenascin [19]. Of the three closely related isoforms (TGF-β1, β2 and β3), TGF-β1 is the most widely studied. All isoforms induce fibroblast proliferation, collagen production and collagen gel contraction. TGF-β synthesis, storage and action are complex. The molecule is secreted as part of a large latent complex from
Anti-IL-5 and asthma
There have been several recent attempts to dissect the role of the eosinophil in asthma by the use of humanised monoclonal antibodies (mAbs) against IL-5. To date, two mAbs against human IL-5, SCH55700 (Schering-Plough Research Institute, www.sch-plough.com) and mepolizumab (GlaxoSmithKline, www.gsk.com), have been used in clinical trials. SCH55700 is a humanised mAb of the IgG4/κ subtype derived from the rat anti-human antibody, 39D10 [24]. Mepolizumab (SB-240563) is a humanised mAb of the
Anti-IL-5 and remodelling
We then proceeded to test the hypothesis that reduction of bronchial mucosal eosinophils with anti-IL-5 would reduce markers of airway remodelling. Bronchial biopsies were obtained before and after three infusions of anti-IL-5 (mepolizumab) in 24 atopic asthmatics in a randomised, double-blind, placebo-controlled study [44]. The thickness and density of tenascin, lumican and procollagen III, in the RBM were measured by confocal microscopy. At baseline, there was airway eosinophil infiltration
Future work
To provide definitive evidence that eosinophils are key cytokines in airway remodelling more effective strategies are required to deplete tissue eosinophils. Even in animal models of asthma, there is residual tissue eosinophilia in the airways after anti-IL-5 administration [59]. In fact, deletion of both IL-5 and eotaxin are required to abolish tissue eosinophils and airway hyper-responsiveness in mice, suggesting that IL-5 blockade alone is insufficient. Combination therapy with, for example,
Acknowledgements
The work is supported by grants from the Wellcome Trust and GlaxoSmithKline. DSR is supported in part by a Wellcome Trust Research Leave Award for Clinical Academics. SP is supported by an International Fellowship from The Royal Society.
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