Associate editor: P.S. Foster
Eosinophil progenitors in allergy and asthma — Do they matter?

https://doi.org/10.1016/j.pharmthera.2008.10.008Get rights and content

Abstract

Allergic inflammation is associated with marked infiltration of eosinophils in affected tissues. The eosinophil is believed to be a key effector cells in allergen induced asthma pathogenesis. However, the role of eosinophils in the clinical manifestation of asthma has recently been questioned, since therapies directed against eosinophil infiltration (i.e. anti-interleukin-5) failed to improve clinical symptoms such as airways hyper-responsiveness (AHR) in patients with asthma. Although eosinophils in peripheral blood and the airways were largely depleted after anti-IL-5 treatment, residual eosinophilia in lung tissue persisted, which permits speculation that the remaining eosinophils may be sufficient to drive the asthma symptomatology. Furthermore, recent findings suggest that primitive eosinophil progenitor cells traffic from the bone marrow to sites of inflammation in response to allergen exposure. These progenitors may then differentiate in situ and thus provide an ongoing supply of mature pro-inflammatory cells and secretory mediators that augment the inflammatory response.

In the present article, we will review the evidence for these findings, and discuss the rationale for targeting hematopoiesis and their migration pathways in the treatment of allergic diseases. Furthermore, this review will highlight the hypothesis that both IL-5- and CCR3-mediated signaling pathways may need to be targeted in order to control the inflammation and AHR associated with asthma.

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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