© 2004 American Thoracic Society
Eosinophil Progenitors in SputumThrowing out the Baby with the Bath Water?Leiden University Medical Center Leiden, The Netherlands One of the least disputed observations in asthma research during the past two decades is the induction of airway eosinophilia after exposure to inhaled allergens in patients who are demonstrating a so-called late asthmatic response (1). The mechanisms underlying such allergen-induced airway eosinophilia have not yet been resolved, and the functional role of these cells in the clinical and physiological expression of the disease has become one of the most disputed issues in asthma research today (2). There is no doubt that major advancements in the prevention and treatment of asthma await conclusive evidence from carefully designed studies in this very area! Therefore, it is good that a (limited) number of distinguished research groups are making steady progress at unraveling the key mechanisms in the maturation and mobilization of eosinophils after allergen-exposure in asthma. In this issue of the Journal (pp. 565–572 and 573–577), Dorman and coworkers present two critical steps in unraveling the kinetics and tissue distribution of eosinophil progenitor cells after allergen challenge in patients with or without late asthmatic responses (3, 4). The first article addresses the eosinophilopoeitic process in bone marrow between 5 and 48 hours after allergen challenge (3). The second article monitors bronchial eosinophil progenitors in induced sputum at 7 and 24 hours after challenge (4). These studies are very complex: they not only require multiple allergen challenges, but also repeated bone marrow aspirates and/or sputum inductions. The perseverance of the investigators and patient volunteers in these studies has generated unique data.
When measuring the time-dependent changes in eosinophil/basophil colony forming units in culture together with cytokine protein levels in bone marrow, it appeared that an increase in IL-3-responsive progenitors (at 5 hours post challenge) preceded a rise in IL-5-responsive progenitors (at 12 and 24 hours) in the patients with late asthmatic responses (3). This was associated with elevated levels of IL-5 (at 12 and 24 hours) and followed by a small increase of interferon-
In the second study (4), the authors were able to demonstrate increases in eosinophil progenitors in induced sputum at 7 and 24 hours after allergen challenge as compared with diluent challenge, both in patients with isolated early and late asthmatic responses. At 24 hours after challenge, the increases in CD34+ cells, in general, and in those cells considered to be eosinophil progenitors (CD34+ cells expressing IL-5R
The challenge here is to integrate these studies. Do the designs and methods allow this? The authors interpret their results in terms of kinetics and trafficking of eosinophil progenitors. However, the connecting element between the two studies (data on the kinetics of progenitors in peripheral blood in both experimental conditions) is missing. Hence, as to whether events in bone marrow and the airways are occurring in parallel or in series remains to be established. Furthermore, changes as observed in eosinophil/basophil colony forming units after 14 days in culture in vitro (3) might differ from those in CD34+ cells expressing IL-5R The most compelling result of these studies is the demonstration of progenitor cells in induced sputum (4). Eosinophil progenitor cell migration from the bone marrow to the airways as well as eosinophilopoiesis in the airway wall is teleologically tenable. But what about progenitor cells leaving the body? Being expectorated before maturation has taken place? Can this simply be regarded as spillover that is dependent on the greater severity of allergic inflammation in patients with late asthmatic responses as compared with patients who only have early responses? Or would the entrance of progenitors into sputum be the result of enhanced active migration (e.g., by eotaxin-CCR3 interaction) as occurs in the bone marrow itself (8)?
Regardless of the mechanism, it is remarkable to note that progenitor cells can behave as lemmings. As with the dynamics of the populations of the lemmings themselves this should be based on phenotype–environment interaction (9). The authors have used IL-5R A highly relevant environmental factor in this process is therapeutic intervention; let us say, the specialist predators against high-density populations (9). Apart from steroids and phosphodiesterase inhibitors, specifically targeted therapy against cytokines and growth factors involved in the differentiation and mobilization of eosinophil progenitors could be an attractive option. Drugs that affect eosinophil development have recently become available for clinical trials. This not only holds for anti–IL-5 that induces a maturational arrest (12), but also for CCR3-antagonists that potentially suppress eosinophil progenitor migration and maturation (13). These experimental approaches will be the opportunity to eventually demonstrate whether the eosinophil and its progenitors are causally related to the clinical expression of asthma. The asthma research community has spent 20 years on this subject (1, 2). This time is relatively short when compared with the 80 years of research by population ecologists preoccupied with fluctuations in numbers of small mammals, such as the puzzling lemming (9). FOOTNOTES Conflict of Interest Statement: P.J.S. is a staff member of the Department of Pulmonology and co-applicant of the following industrial research grants to the Department of Pulmonology: Altana Pharma ($202,616), Novartis ($90,640), Bayer ($61,762), AstraZeneca ($103,153), and GlaxoSmithKline ($299,495) in the years 2000–2003. P.S.H. is a staff member of the Department of Pulmonology and co-applicant of the following industrial research grants to the Department of Pulmonology: AstraZeneca (€37,000 and €162,000) during 2000–2003. REFERENCES
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(48 hours) in bone marrow. No such changes were observed in patients with early asthmatic responses. This suggests a differential regulation of subsequent phases of eosinophilopoiesis in bone marrow after allergen challenge in asthma. 
) were significantly larger in the late responders as compared with the early responders, which was associated with sputum eosinophil counts at 24 hours and sputum IL-5 levels measured at an earlier time point (7 hours). This confirms and extends previous observations of in situ eosinophylopoiesis in the bronchial mucosa (