The Big Asthma Lie

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Th2-type cytokines such as IL-4, IL-5, and IL-13 orchestrate a cascade of events during development of an allergic inflammatory response. This is demonstrated both clinically and in preclinical animal models (404, 405). IL-4 plays a critical role in the early commitment of ThO cells to Th2 cells and regulates IgE secretion by B-cells. It also induces V-CAM expression on endothelial cells, promotes eosinophilic inflammation, and increases airway mucus production.

In asthmatic patients there is an increase in serum and bronchoalveolar lavage fluid IL-4 levels, and atopic individuals have a higher frequency of IL-4-producing T-cells (406, 407). Genetic studies have linked asthma and atopy to the chromosome region 5q31-33, which includes IL-4, IL-5, IL-9, and the IL-13 genes (408). Thus, aberrant production of IL-4, or excessive response to this cytokine resulting from genetic defects, might contribute to the pathogenesis of asthma.

IL-4 is a 20-kDa secreted glycoprotein and its expression is highly tissue specific. IL-4 is produced by Th2 cells and natural killer cells in response to stimulation through the T-cell receptor (409). IL-4 binds to two types of receptor complexes, type I and type II receptors. Type I receptor complexes are formed by the IL-4 receptor a chain (IL-4Ro:) and the common y chain (yC), whichform part of the many other cytokine receptor complexes. The type II receptor consists of the IL-4Ra chain and the IL-13R« chain. In both cases signaling occurs through the JAK/STAT pathway, more specifically through activation of STAT6 (410).

9.3.1 IL-4 Knockout and Transgenic Mice.

In general terms IL-4 and IL-4Ra knockout mice show similar phenotypes. Both develop normally but they show a clear deficiency in the Th2 response (411-413). They are able to mount antibody responses but show a significant decrease in their ability to generate IgE and IgGl. In addition they show a decreased capability to expulse intestinal parasites

Transgenic mice expressing IL-4 in different tissues have been generated. When IL-4 expression is targeted to T-cells, they present increased airway hyperreactivity, inflammation in the eye, and mild B-cell hyperplasia

(415). If IL-4 is targeted to the airway epithelium, an enhancement of goblet cell hyperplasia is observed (416). These experiments showed the multiple functions IL-4 can exert over different cell types.

9.3.2 IL-4 Modulators/Clinical Data. Dif ferent approaches have been taken to neutralize IL-4 activity, including soluble IL-4 receptor, antibodies against IL-4, and mutated IL-4, which acts as an antagonist of the receptor. In a mouse model of airway inflammation, soluble IL-4 receptor administered intranasally, before allergen challenge, results in a reduction of eosinophil infiltration, V-CAM expression, and mucus hypersecretion (417). This treatment, however, did not change airway hyperreactivity in response to methacholine.

In another mouse model of allergic lung inflammation, antibodies against IL-4 administered during sensitization reduce or abolish airway eosinophilia and airway hyperreactivity (418,419).In similar mouse models, a mutant form of murine IL-4 (Q116D/Y119D), acting as both IL-4 and IL-13 antagonist, was found to abrogate the humoral immune response to allergen challenge, and completely inhibited synthesis of allergen-specific IgE and IgGl (420). Another murine IL-4 mutant (deletion mutant CI 18), showing similar antagonism against IL-4 and IL-13, inhibited the development of airway eosinophilia and airway hyperreactivity (421). These results suggest that a dual IL-4/IL-13 antagonist could be highly efficacious for the treatment of asthma. Similar mutations have been described for human IL-4 and shown to be efficacious at inhibiting IL-4 and IL-13 responses in vitro (422).

As mentioned earlier, soluble receptors are another means to antagonize cytokine activity. The soluble IL-4R (Nuvance, Immunex Corporation) consists of the N-terminal region of the IL-4Ra chain and has been shown to bind IL-4 and sequester this circulating cytokine. Nuvance was tested in a clinical trial with promising results (423). The drug was well tolerated and the placebo group showed a decline in FEV1 not observed in the treated group. The efficacy of Nuvance TM was confirmed by improved asthma symptom scores in the treated group compared to those of placebo. In spite of these promising results, Im-munex had announced that Nuvance failed to show efficacy in two Phase II clinical trials. A third trial is still ongoing.

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Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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