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【Am J Respir Crit Care Med】Magic Bullets The New Goal for
Woodruff and colleagues have previously described an asthma-specific mRNA signature in epithelial cells . The three most highly expressed genes were periostin, Serpin B2, and CLCA1. These genes are induced by Th2 cytokines, and their role in the pathogenesis of asthma is under investigation. Although these genes are up-regulated in asthma, this mRNA signature is not uniformly expressed in disease. Using cluster analysis, Woodruff and colleagues found that subjects with asthma could be divided into two groups with high or low expression of these genes, which they proposed represent Th2 high and Th2 low phenotypes . Indeed, Th2 cytokine expression was increased in bronchial biopsy homogenates from subjects with asthma that expressed the epithelial gene signature. Those subjects with asthma in the Th2 high group had increased airway and peripheral blood eosinophils, total IgE, airway hyperresponsiveness (AHR), and thickening of the lamina reticularis. This is consistent with previous reports that eosinophilic inflammation is related to features of remodelling . Interestingly, in contrast to eosinophilic versus noneosinophilic asthma , molecular phenotyping identified a highly significant, albeit small, increase in AHR in the Th2 high group. Eosinophilic airway inflammation and AHR can be dissociated, as in nonasthmatic eosinophilic bronchitis , and AHR is unaffected by anti-IL-5 monocloncal antibody therapy despite marked reductions in eosinophilic inflammation . This suggests that Th2 cytokines, independent of eosinophilic inflammation, may be important in the development and persistence of AHR.
It is not sufficient for new asthma phenotypes to simply provide an alternative to traditional classification. These phenotypes need to generate new insights into disease pathogenesis, identify responders to current and future therapy, and predict disease progression. To date the presence of eosinophilic inflammation has been the most valuable biomarker to predict response to corticosteroid therapy . Two recent studies of anti-IL-5 therapy have demonstrated efficacy in severe asthmatics with evidence of persistent eosinophilic airway inflammation, allowing the successful withdrawal of systemic corticosteroid therapy in previously prednisone-dependent patients with asthma .as well as a 43% reduction in severe exacerbations . Interestingly, the reduction in exacerbations was not associated with benefits in day-to-day symptoms or lung function. Such results highlight the importance of patient selection, as highly specific therapies are likely to only have efficacy in patients with asthma for whom the target of interest is a dominant component of their disease. In keeping with these observations, subjects with a Th2 high phenotype had a favorable response to corticosteroids . This phenotype was stable in subjects treated with placebo, but there was a shift to a Th2 low phenotype after corticosteroid therapy, perhaps suggesting that the validity of this technique may be limited to corticosteroid naïve subjects with asthma. Importantly, the healthcare challenge is greatest in those with severe asthma. Therefore, whether the Th2 high phenotype identifies a group of subjects with severe asthma who responds to other specific anti-Th2 cytokine therapy needs to be examined. Lessons from studies with anti-IL-5 suggest that potential efficacy may be restricted to specific clinical outcomes, so clinical trials of new treatments will need to be interpreted with caution.
Much attention has been given to the Th2 axis in asthma and several speciic therapies are in early clinical trials . The identification of a Th2 low group of subjects with asthma is akin to the earlier identification of noneosinophilic asthma . This group has a relatively poor clinical response to corticosteroids and potentially represents an important unmet need for therapy. The etiology of Th2 low asthma is uncertain. However, studies in noneosinophilic asthma suggest that factors acting through the innate immune pathway, such as environmental exposure to bacterial endotoxin, particulate air pollution, ozone, and persistent infections, may play a role. Early trials of macrolide therapy have shown promise and whether the Th2 low group is amenable to this strategy or perhaps to more specific antineutrophil approaches needs to be examined.
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作者:admin@医学,生命科学 2010-11-23 05:11
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