Reviews and feature articles
Eosinophil trafficking in allergy and asthma

https://doi.org/10.1016/j.jaci.2007.03.048Get rights and content

Blood eosinophilia and tissue eosinophilia are characteristic features of allergic inflammation and asthma, conditions associated with prominent production of TH2 cytokines IL-4, IL-5, and IL-13. In this review, we will consider recent advances in our understanding of the molecular mechanisms that promote expansion and differentiation of eosinophil progenitors in bone marrow, eosinophil recruitment in response to chemokine receptor 3 agonists eosinophil transit mediated by specific ligand-receptor interactions, and prolonged survival of eosinophils in peripheral tissues. Novel rational therapies including antiselectin and antichemokine receptor modalities designed to block eosinophil development and trafficking are discussed, together with the implications of recent clinical studies that have evaluated the efficacy of humanized anti–IL-5 mAb therapy.

Section snippets

A caveat on human versus mouse eosinophils

It is important to recognize that most of the findings to be discussed result from work performed in mouse models of disease. Although all investigations can suffer from overinterpretation of cross-species findings,11, 12 the problems are particularly large when examining results related to the eosinophil. Although mouse eosinophils, like human eosinophils, can be identified by red-staining granules in blood, bone marrow, and tissue preparations stained either with hematoxylin and eosin or

Eosinophil expansion in response to allergic provocation

An allergic response is initiated in situ as a CD4+ naive T lymphocyte responds to specific stimulation by developing into a TH2 lymphocyte. TH2 lymphocytes synthesize and secrete the cytokines IL-4, IL-13, and IL-5. IL-4 promotes eosinophilia indirectly via promoting autocrine development of TH2 lymphocytes, and murine eosinophils themselves produce IL-4.19, 20 Human eosinophils express IL-4 receptor α (IL-4Rα).21, 22 IL-4 also activates human vascular endothelial and respiratory epithelial

The pivotal role of IL-5

The TH2 cytokine IL-5 is a central factor mediating eosinophil expansion, priming, recruitment, and prolonged tissue survival in response to allergic stimuli. Originally identified as murine T-cell replacing factor, a B-cell growth factor and eosinophil differentiation factor, IL-5 is synthesized predominantly by TH2 lymphocytes, but in smaller amounts by mast cells and eosinophils. IL-5 promotes differentiation of terminally committed human and murine eosinophil precursors in bone marrow.28, 29

Eosinophil development in the bone marrow

Committed eosinophil progenitors are derived from pluripotent CD34+ stem cells found in normal bone marrow. Of note, committed CD34+IL-5R+ eosinophil progenitor cells have also recently been identified in murine lung tissue.34 Studies of ex vivo bone marrow cultures have shown that eosinophils develop from these progenitors in response to GM-CSF, IL-3, and IL-5. When they are phenotypically mature, eosinophils are released from the bone marrow into the circulation.

As noted, IL-5 is a strong and

Eosinophil transit into tissues

Mature eosinophils leave the bone marrow and are attracted to sites of allergic inflammation by the actions of proinflammatory chemokines, which are produced in response to allergic stimulation by endothelial and epithelial cells activated by, among other mediators, IL-4 and IL-13. Eosinophils express receptors for the CC group of chemokines (those that contain adjacent cysteines near the amino terminus). Several CC chemokines have been characterized as eosinophil chemoattractants, including

Eosinophil survival and apoptosis

A final aspect of eosinophil trafficking involves its survival and functioning within peripheral tissues. There are several excellent reviews that detail general findings relating to apoptosis signaling pathways described in eosinophils.74, 75, 76 Among the findings that relate uniquely to the biology of eosinophils, IL-5 clearly promotes eosinophil survival in vitro, and the absence of IL-5 results in spontaneous cellular apoptosis. Simon et al76 and Simon77 have shown that IL-5 is also

Clinical implications

Given the pivotal role of IL-5, it seemed reasonable to assume that blockade of IL-5 would result in the elimination of eosinophilia and thus the reduction in symptomatology associated with allergic asthma. This hypothesis was tested in clinical trials using 2 humanized monoclonal anti–IL-5 antibodies, SCH55700 (Schering-Plough Research Institute, Kenilworth, NJ) and mepolizumab (GlaxoSmithKline, Middlesex, United Kingdom). In a randomized, double-blind study of mepolizumab, clinical symptoms

Conclusion and future directions

Despite some controversial findings, the balance of data suggests that eosinophils promote 1 or more aspects of respiratory dysfunction characteristic of allergic asthma. As such, the possibility that drugs directed at inhibition of eosinophil migration or activation or even outright eosinophil ablation might prove to be effective therapeutic strategies certainly remains worthy of further exploration. Among the avenues that might be considered is the possibility that coordinate inhibition of

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    (Supported by an unrestricted educational grant from Genentech, Inc. and Novartis Pharmaceuticals Corporation)

    Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, William T. Shearer, MD, PhD, and Donata Vercelli, MD

    Disclosure of potential conflict of interest: S. Phipps has received grant support from the Australian Lung Foundation. H. F. Rosenberg and P. S. Foster have declared that they have no conflict of interest.

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