© 2003 American Thoracic Society
Is the Eosinophil a "Humpty Dumpty" Cell in Asthma?Department of Medicine University of Wisconsin Medical School Madison, Wisconsin Eosinophilic infiltration is a characteristic feature of asthma, and based upon the eosinophil's biological actions, this cell had assumed a prominent position as a, if not the, principal inflammatory cell in asthma. (1) These apparently well-substantiated assumptions, however, came under considerable suspicion when Leckie and coworkers (2) evaluated the effect of anti–interleukin (IL)-5 monoclonal antibody administration on the airway response to inhaled antigen. These investigators found the usual increase in peripheral blood and sputum eosinophils to inhaled antigen was nearly abolished by anti–IL-5 treatment. In contrast to studies in animals (3, 4), anti–IL-5 in human asthma did not affect either the immediate- or late-phase response to antigen or the expected increase in post–allergen-induced airway hyperresponsiveness. Based upon these observations, the authors questioned the "prerequisite" role of eosinophils in the late asthmatic response to inhaled antigens and its "relevance to the pathogenesis and treatment of asthma." Indeed, Humpty Dumpty had taken a great fall. An Editorial by Boushey and Fahy (5), which accompanied the publication by Leckie and colleagues (2), went so far as to suggest that, "The finding that a reduction in number of blood and airway eosinophils was not associated with a reduction in allergen-induced bronchoconstriction or hyperreactivity challenges the hypothesis that the eosinophil is a central effector cell in asthma. The eosinophilic response and the physiological responses to allergen challenge seem to be separable. The blocking of eosinophil production or migration may thus be of little benefit as therapy for asthma." Putting the eosinophil "back together again" in the complexity of asthma pathophysiology now appeared unlikely. However, as pointed out by O'Byrne and colleagues (6), the study by Leckie and coworkers (2) had limitations in statistical power, and the lack of effects of IL-5 on airway hyperresponsiveness was questionable. Thus, lines of debate and inquiry were established to determine whether, and how, the eosinophil participates in allergic inflammation and asthma. The contribution of eosinophils to host-defense and inflammatory responses has undergone periodic re-evaluations. Thirty years ago, the eosinophil was considered as a principal effector cell in host–defense against parasites (7). Furthermore, the actions of eosinophil enzymes, like histaminase, were felt to suppress mast cell-released allergic mediators. As the biological repertoire of the eosinophil became more apparent, this cell's inflammatory potential was established, and its toxic properties were causatively linked to a variety of pathophysiologic events in asthma: inflammation, epithelial injury, and hyperresponsiveness (1). In addition, a number of cytokines, particularly IL-5, were found to be critical in eosinophil growth, terminal differentiation, and survival. In animal models and humans, the expression and production of IL-5 correlated with eosinophil recruitment to the airway following antigen challenge (8, 9). In animal models, modulation of IL-5 activity by monoclonal antibodies or gene knockout experiments reduced circulating and airway eosinophils, and inhibited the pulmonary physiologic responses relevant to allergen challenge: airflow obstruction and bronchial hyperresponsiveness (4, 8, 10). Furthermore, the inhalation of IL-5 by subjects with asthma increased bronchial eosinophilia and airway hyperresponsiveness (11). Collectively, a strong linkage between IL-5 generation, eosinophilic inflammation, and pathophysiologic events in asthma emerged. Thus, the observations of Leckie and coworkers (2) were of considerable surprise, but the eosinophil tumbled from its status in asthma. In this issue of AJRCCM (pp. 199–204), Flood-Page and colleagues (12) have begun critical reassessments to re-explore the role of eosinophils and IL-5 in asthma. In their well-designed study, IL-5 monoclonal antibody or placebo was administered to 24 subjects with asthma. As noted by Leckie and coworkers (2) and in animals studies (4), anti–IL-5 treatment nearly ablated circulating and bronchial lavage fluid eosinophils. In contrast, Flood-Page and coworkers (12) found anti–IL-5 reduced bone marrow eosinophils by only 52%, and in mucosal biopsies, the eosinophil reduction was only 55%. Moreover, the deposition of eosinophil major basic protein in mucosal tissue was unaffected by anti–IL-5 therapy. Although no changes in airway responsiveness followed anti–IL-5 administration, slight improvements in morning peak expiratory flow occurred. The findings of Flood-Page and coworkers (12) revealed a number of important aspects of eosinophil biology in asthma. First, the eosinophil is present in different compartments (i.e., circulation, airway tissues, and bone marrow) and eosinophils in each of these compartments have a different susceptibility to therapeutic interventions and possibly distinct actions on airway function. Second, the resistance of eosinophil major basic protein to anti–IL-5 treatment further suggests that eosinophil injury may be "permanent," despite the eradication of this cell in the circulation or airway lumen. Third, certain biological compartments (e.g., bone marrow and airway tissue) appear to be "privileged," or protected, from anti–IL-5's anti-eosinophilic treatment, and the persistence of eosinophils in these locations may indicate why airway physiology outcomes are resistant to anti–IL-5 treatment. Another important aspect of this apparent resistance of tissue eosinophils to anti–IL-5 treatment may be related to decreased expression of IL-5 receptor. We have recently demonstrated that, compared with their circulating counterparts, airway eosinophils have markedly reduced cell surface IL-5 receptor, which is associated with loss in their capacity to degranulate to IL-5 (13, 14). These findings suggest that IL-5's contribution to eosinophil biology may be limited to recruitment to the airway. Finally, other cytokines/chemokines, including eotaxin, regulated upon activation, normal T cell expressed and secreted (RANTES), IL-3, and granulocyte–macrophage colony-stimulating factor, may assume importance in regulating eosinophil function. (15) Controversy can be constructive and lead to eventual clarification of the eosinophil's role in asthma as old concepts and prejudices are critically re-examined. As "all the King's horses and all the King's men" now work to put "Humpty Dumpty (i.e., the eosinophil) together again," a refined and more accurate role of this cell and its relationship to inflammatory cell networks, pulmonary physiology, and, ultimately, clinical asthma will emerge. Flood-Page and coworkers (12) have initiated this process of rediscovery. REFERENCES
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