© 2003 American Thoracic Society
Eosinophils and Interleukin-5The Debate ContinuesDepartment of Allergy and Clinical Immunology Imperial College National Heart and Lung Institute London, United Kingdom For over 20 years, we have speculated that eosinophils are key effector cells in the pathogenesis of asthma (1). The discovery of interleukin (IL)-5, a cytokine that is essential for terminal differentiation of the committed eosinophil precursor (2), which also activates (3) and prolongs survival of the mature cell in the tissues (4), offered an opportunity to test this eosinophil hypothesis. Leckie and coworkers, however, surprisingly found that a monoclonal antibody directed against IL-5 (mepolizumab) had no effect on either the late asthmatic reaction or airway hyperresponsiveness after infusion in patients with mild atopic asthma (5). One explanation for these findings was that these patients' asthma was too mild to show an appreciable clinical effect of eosinophil depletion and that this form of treatment would only be effective in subjects with more severe disease. In this issue of AJRCCM (pp. 1655–1659), Kips and coworkers (6) describe the effects of a second humanized anti–IL-5 monoclonal antibody (SCH55700). Their patients had severe asthma with persistent symptoms despite high-dose inhaled corticosteroids and/or oral prednisolone. Volunteers received a single infusion of SCH55700 or placebo in a double-blind fashion, and blood and sputum eosinophils, spirometry, peak flow recordings, and symptoms were monitored for up to 30 days. In agreement with data obtained with the other anti-IL-5 antibody, mepolizumab (5, 7), SCH55700 produced a significant decrease in blood eosinophil counts at the two highest doses used. Unfortunately, insufficient paired samples were obtained to determine whether SCH55700 had any appreciable effect on sputum eosinophils. The 0.3-mg/kg dose of SCH55700 produced a significant increase in FEV1 at 24 hours, which persisted as a trend at subsequent time points. This improvement was not associated with changes in symptom scores, FEV1/FVC ratio, or peak flow recordings. Therefore, the rapid improvement in FEV1 is difficult to interpret, and the fact that it was not sustained and only observed with the submaximal dose was disappointing. This finding may have been related to the more acute bronchoconstricting effect of eosinophil-derived cysteinyl leukotrienes or even to an eosinophil-independent property as airway smooth muscle cells express the IL-5 receptor and in vitro incubation with IL-5 selectively primes for hyperresponsiveness (8). Thus, the rapid improvement in FEV1 may have been due to direct blockade of the actions of IL-5 on airway smooth muscle, which in turn improved airway caliber. The eosinophil may have a role not only in acute/subacute processes involved in airway narrowing but in more downstream events, such as repair and remodeling resulting from chronic eosinophilic inflammation. In this regard, it is of interest that even modest eosinophil depletion by anti–IL-5 was associated with significant reductions in tenascin and lumican deposition in the bronchial reticular basement membrane (9). Therefore, studies designed to test the effect of eosinophil depletion on repair and remodeling may provide further information on the role of this cell in asthma. The article by Kips and coworkers (6) was a small phase II study that was not powered to detect changes in clinical variables. Larger trials may reveal an effect of IL-5 blockade in different subgroups because asthma is a heterogeneous condition, and some patients may have disease that is largely eosinophil driven. Nevertheless, it might be easy to lump these data with the previous anti–IL-5 clinical studies as further evidence of a minimal or negligible role for eosinophils in the pathogenesis of asthma. Before reaching this conclusion, it is important to establish that depletion of blood eosinophils is actually indicative of a similar reduction of this cell type in the bronchial mucosa. Flood-Page and coworkers (7) observed a significant differential effect of IL-5 blockade on eosinophil counts in various body compartments. After multiple dosing with mepolizumab, there was a 100% median reduction in eosinophils in blood, 79% in bronchoalveolar lavage, but only a 52% in the bone marrow and a 55% decrease in the bronchial mucosa. This study clearly demonstrated that a dramatic depletion in blood eosinophils was associated with only a modest change in the bronchial mucosa and emphasized the importance of obtaining biopsy tissue from the target organ when evaluating eosinophil-depleting strategies.
The exact reason for a different effect of anti–IL-5 in one compartment as opposed to another is unclear, but it may be due to varying IL-5 sensitivity and a level of expression of the IL-5 receptor at different time points in the cell's formation, function, and fate. Liu and coworkers showed that IL-5 receptor expression on airway eosinophils is downregulated in vivo after inhaled allergen challenge and that this was associated with a loss of IL-5 responsiveness (10). In addition, Gregory and coworkers (11) have demonstrated that exposure of blood eosinophils to IL-3, IL-5, or granulocyte-macrophage colony-stimulating factor in vitro leads to sustained downregulation of surface IL-5 receptor From all of this information, it is reasonable to conclude that anti–IL-5 monoclonal antibodies are ineffective at depleting tissue eosinophils and that this strategy may be fundamentally flawed. Even in animal models of asthma, there was residual tissue eosinophilia in the airways after anti–IL-5 administration (12). Foster and coworkers (13) have reported that deletion of both IL-5 and eotaxin are required to abolish tissue eosinophilia and airway hyperresponsiveness in BALBc mice, suggesting that IL-5 blockade alone is insufficient to abrogate the tissue eosinophilia associated with allergic inflammation. Combination therapy, for example, anti–IL-5 and a CCR3 antagonist, may be more useful than IL-5 blockade alone, as this would have the theoretic advantage of inhibiting both bone marrow maturation (mainly an IL-5 effect) and tissue accumulation (predominantly a CCR3-dependent effect). In summary, the study by Kips and coworkers (6) provides further evidence that anti–IL-5 is not a magic bullet for asthma. However, it would be unwise to downplay totally the eosinophil's potential in the asthma process until we have effective and selective methods of depleting the cell from the tissues. REFERENCES
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-chain expression and reduced responsiveness to IL-5 but with no sustained changes in CCR3 expression. 
