Associate editor: P.S. FosterEosinophil progenitors in allergy and asthma — Do they matter?
Introduction
The prevalence of asthma and other allergic diseases is a major public health problem in Westernized countries, and the current trend indicates the possibility of a further increase (Beasley et al., 2000). Allergic asthma is associated with pronounced inflammatory changes in the airways, including increased numbers of lymphocytes, neutrophils, mast cells and maybe most important, eosinophils. Eosinophilia is a hallmark of a number of allergic disorders including rhinitis, atopic dermatitis and asthma.
The inflammatory process that occurs following allergen exposure can be divided into several distinct steps, one of which is activation of the bone marrow, resulting in both the release of eosinophils into the circulation and the production of new eosinophils (Broide et al., 1992, Foster et al., 1996). Accumulation of eosinophils within the airways is most likely a combination of migration, prolonged survival and an increased production of these cells in the bone marrow. A growing body of evidence suggests that not only mature eosinophils but also immature precursors (CD34+ cells) and eosinophil-committed progenitors (CD34+/IL-5Rα+ cells) are recruited to the sites of inflammation following allergen exposure, augmenting the degree of tissue inflammation (Sehmi et al., 1996, Palframan et al., 1998a, Palframan et al., 1998b).
In this review, we will highlight the findings which relate to the role of eosinophil progenitors in promoting allergic inflammation and consider the possibility that suppression of these progenitors may be necessary to control allergen induced airway inflammation.
Section snippets
Eosinophils in allergy and asthma
Eosinophils are multifunctional leukocytes involved in a diverse number of inflammatory processes including helminth infections and allergic diseases (Gleich and Loegering, 1984, Weller, 1994, Rothenberg, 1998). In response to stimuli, such as helminth or allergen exposure, eosinophils are recruited from the circulation to sites of inflammation. The trafficking of eosinophils to inflammatory sites is coordinated by a wide range of cytokines, chemokines and adhesion molecules (Bochner and
Progenitor cells
Hematopoietic progenitors are defined as undifferentiated pluripotent stem cells capable of self renewal and differentiation into all blood cell types, as well as cells characterized by limitless capacity for self renewal (Szilvassy & Hoffman, 1995).
The majority of hematopoietic activity takes place in the bone marrow, under the influence of resident stromal cells as well as T-lymphocytes and monocytes and their products (Mayani et al., 1992) (Fig. 1). One important marker of hematopoietic
Evidence for a role of eosinophil progenitor cells in allergic airway inflammation
Over the last decade, a growing body of evidence has emerged implicating a role for eosinophil progenitors in allergic inflammation in both human as well as animal models. Eosinophil progenitors are increased in the peripheral blood in patients with allergic rhinitis, nasal polyps and asthma compared to non allergic individuals (Gibson et al., 1990, Gibson et al., 1991, Sehmi et al., 1996, Sehmi et al., 1997, Robinson et al., 1999a). Importantly, an increased number of CD34+ cells expressing
Systemic signaling between the lung and bone marrow
Allergen induced airway inflammation results in enhanced bone marrow eosinophilopoiesis in asthmatic subjects as well as in animal models of allergen-induced airway inflammation (Woolley et al., 1994, Sehmi et al., 1996, Gaspar Elsas et al., 1997, Ohkawara et al., 1997, Sehmi et al., 1997, Tomaki et al., 2000, Wood et al., 1998a, Wood et al., 1998b). However, the mechanisms of the activation of the bone marrow following airway allergen exposure are not completely understood. Although the nature
Targeting eosinophils and their progenitors for therapy
Until recently, eosinophils were thought to be a key effector cells in the pathogenesis of asthma. However, the role of the eosinophil in asthma has been questioned over the last decade, since lack of effect of anti-eosinophilic therapies on clinical parameters seen in asthma has been demonstrated (Leckie et al., 2000).
Two monoclonal antibodies against IL-5, SCH55770 (Schering-Plough Research Institute) and Mebolizumab/SB-240563 (Glaxo SmithKline) have been used in clinical trails. Treatment
Conclusions and future considerations
In summary, the results of the clinical studies using humanized monoclonal anti-IL-5 clearly demonstrate that eosinophils are capable of persisting in lung tissue despite effective IL-5 blockade. These findings highlight the possibility that additional, not-yet clearly identified signals may promote eosinophil survival in vivo in response to allergen challenge, which need to be investigated further. Eosinophil progenitors recruited to the lung tissue, may contribute to this process by
Acknowledgments
The authors are grateful to Dr Helene Rosenberg, Eosinophil Biology Section, Laboratory of Allergic Diseases, NIAID/NIH, Bethesda, for invaluable and helpful discussions and suggestions during the development of the manuscript, and for reviewing the manuscript.
The authors are supported by the Swedish Heart and Lung Foundation. Dr Madeleine Rådinger is in part supported by the Division of Intramural Research, National Institute of Allergy and Infection Diseases.
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2017, Pharmacology and TherapeuticsCitation Excerpt :It plays a central part in differentiation and maturation of eosinophils in bone marrow, and IL-5 priming induces eosinophil locomotor activity, suggesting that it might play a role in eosinophil recruitment to inflamed pulmonary tissues (Sehmi et al., 1992; Wen et al., 2013; Larose et al., 2014). IL-5 stimulates activation and degranulation of eosinophils; enhances their survival in tissues (Ochiai et al., 1997; Huang et al., 2005); and promotes eosinophilic precursors to proliferate, differentiate and function independently in various tissues, including the lung (Robinson et al., 1999a, 1999b; Lu et al., 2010; Dorman et al., 2004a, 2004b; Rådinger & Lötvall, 2009; Fulkerson et al., 2014). IL-5 expression is elevated in bronchoalveolar lavage fluid and bronchial biopsies from asthmatic patients with eosinophilic pulmonary inflammation (Hamid et al., 1991; Kim et al., 2003; Huang et al., 2005).
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2015, International ImmunopharmacologyCitation Excerpt :Eosinophils are recruited from the circulation to inflammatory tissues in response to allergic stimuli, and they are the predominant inflammatory cells in asthmatic lung tissues. It was suggested that eosinophils contribute to the pathogenesis of allergic asthma including tissue damage and AHR [28]. In the lungs, endothelial cells, smooth muscle cells, epithelial cells, alveolar macrophages, and eosinophils can produce eotaxin.