Trends in Pharmacological Sciences
Reassessing the Th2 cytokine basis of asthma
Section snippets
T-helper cells in allergic asthma
The association of peripheral blood lymphopenia (a decrease in the number of lymphocytes) with increases in the number of eosinophils and the level of IgE in allergic asthmatics was made almost 30 years ago [6]. Several years later, Parish and Luckhurst [7] reported that T cells obtained from the airways, but not the peripheral blood, of asthmatic subjects released mediators that promoted eosinophil, but not neutrophil, chemokinesis and chemotaxis. Around this time a functional differentiation
Efficacy of anti-IL-5 antibodies and the soluble IL-4 receptor in asthma
To evaluate the role of IL-4 and IL-5 in asthma, it was necessary to develop antagonists for these cytokines. Efforts to do this resulted in the development of humanized monoclonal antibodies (hMAbs) directed against IL-5 and a recombinant human soluble IL-4 receptor as an IL-4 antagonist. These molecules were initially validated in mouse models of allergic inflammation and were then evaluated in asthmatic patients (Table 1). In one study, 24 mild allergic asthmatic subjects were treated with
The Th2 hypothesis in asthma is alive, but ailing
There is, as yet, insufficient information about the efficacy of the soluble IL-4 receptor and the anti-IL-5 MAbs in the treatment of asthma to draw firm conclusions about the importance of IL-4 and IL-5 in asthma pathogenesis, and to evaluate the credibility of the Th2 hypothesis for allergic asthma. It is clear, however, from studies evaluating the hMAb directed against the high-affinity IgE receptor (FcϵR1) (omalizumab) that the presence of high levels of IgE plays an important role in the
Concluding remarks
The Th2 cytokines, such as IL-4, IL-5 and IL-13, remain likely to be of central importance in the pathogenesis of allergic asthma. The lack of a striking benefit demonstrated with the hMAbs against IL-5 either in protecting against allergen inhalation challenge or in moderate to severe asthma does not exclude a potential role for IL-5 or eosinophils in asthma. The study designs and/or the patient populations chosen for these trials limit the possibilities for interpretation of results. Despite
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