Eosinophilopoiesis at the cross-roads of research on development, immunity and drug discovery.

Eosinophils are a minority subpopulation of leukocytes whose roles in host defense against infection remain controversial, but which have been implicated in the pathogenesis of both acute allergic inflammation and the chronic bronchopulmonary remodelling in asthma. Eosinophilia, a hallmark of both helminth infections and atopic diseases, is maintained through upregulation of eosinophilopoiesis by means of increased production and effectiveness of Interleukin-5 (IL-5), a major Th2 cytokine. These mechanisms are further modulated by a wide variety of agents, including glucocorticoids, nonsteroidal anti-inflammatory drugs and mediators of inflammation. We review recent progress made by different groups in the study of eosinophilopoiesis that led to the identification of the heterogeneous targets for developmental regulation by IL-5 and other agents, and to the ongoing characterization of the molecular mechanisms that ensure their commitment to the eosinophil lineage. We argue that the study of eosinophilopoiesis provides insight into basic developmental processes, and especially into how modulators influence the constitutive rate of eosinophil production by controlling the rates of apoptosis and terminal differentiation. The mechanisms underlying the apparently paradoxical effects of dexamethasone, a drug widely employed to control inflammation, as well as the role of specific molecular targets (including inducible NO synthase and CD95/Fas) in developmental regulation, are discussed in detail. We further argue that eosinophilopoiesis offers unique insights of how immune and endocrine effector loops interact to control both the steady-state responses to IL-5 and the susceptibility to modulation of these responses by drugs and cytokines. We also review the existing evidence on the recruitment of circulating stem cells and progenitors into inflammatory sites, and on a critical role for IL-5 in the accumulation of eosinophil lineage-committed progenitors in lungs of allergic mice. Finally, we review recent progress in the study of the regulatory T cell populations present in bone-marrow, and discuss alternative mechanisms through which cellular immunity may influence eosinophilopoiesis.

The effects of allergen and anti-allergic drugs on murine hemopoietic cells: moving targets, unusual mechanisms, and changing paradigms.

We used a variety of techniques to evaluate the effects of airway allergen exposure in mice on the responses of hemopoietic cells to cytokines and drugs in vitro and in vivo. Initial studies have shown that allergen exposure of sensitized mice leads to release of circulating mediators, that induce rapid upregulation of bone-marrow responses to IL-5 and GM-CSF. This may be related to glucocorticoids, because exogenous dexamethasone has similar effects on cultured murine bone-marrow, and because stress-induced glucocorticoids, in naïve or sensitized mice, have effects indistinguishable from those of allergen challenge in sensitized animals. Upregulation of eosinophil production is associated with an increased expression of alpha4 integrins, which may contribute to retention of these cells in the bone-marrow. Glucocorticoids regulate the adhesiveness, maturation and survival of eosinophils in murine bone-marrow culture, partly by counteracting the actions of Prostaglandin E2 and possibly other prostanoids. Allergen exposure of sensitized mice leads to accumulation of hemopoietic progenitors in the lungs, which differ from those in bone-marrow in growth properties and sensitivity to glucocorticoids. Lung transplantation has been used to demonstrate that the lung acts as a source of endocrine factors that promote hemopoietic cell accumulation, independently of damage caused by local allergic inflammation.