Current Drug Targets - Inflammation & Allergy - Volume 2, Issue 4, 2003

Sometimes an opportunity arises to survey a rapidly developing field of specialized research just before it begins to attract more widespread attention. It is my feeling that this applies to the role of hemopoietic cells and hemopoietic factors in allergy and asthma, which constitutes the theme of this Hot Topic issue. For a decade now, this issue has been explored by a number of dedicated specialists, who have repeatedly drawn our attention to the fact that hemopoiesis continually provides allergic inflammation sites with novel cells, and thereby plays an essential role in the chronicity of allergic disease. Over the last few years, this view has been refined to include an ever growing awareness of the pathogenetic potential of hemopoietic factors which had been originally described in a context quite foreign to allergy and asthma, as is the case with Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF), Interleukin-5 (IL-5) and Stem Cell Factor (SCF). As it turns out, hemopoietic factors do much more in allergy than command the replenishment of infiltrating leukocytes. The diverse roles of GM-CSF include its essential participation as an instructive signal in the initiation of allergic sensitization itself. It also operates as a critical interface between the organism and its environment, since it is induced by a variety of environmental influences known by their association with the explosive growth of allergic diseases in recent years. SCF has proven no less protean in its actions, for it not only orchestrates the development and function of mast cells but displays an amazing plasticity in regulating them, for it interacts with the diverse signals converging on mast cells to provide remarkably diverse outcomes. In both cases, the issue of the role of hemopoietic factors in allergy has been given an unexpected answer, as it appears that hemopoietic factors are important, but not in conventional sites of hemopoiesis. The research in this field is, in my view, approaching a new turning point, as it becomes clear that the hemopoietic cells found in sites of allergic inflammation differ in some important ways from those found in the bone-marrow. Several groups have now concentrated in the study of the various types of hemopoietic progenitor and precursor cells that accumulate in the circulation and tissues of allergic subjects. As discussed in this issue, these have turned out to have unusual and interesting properties. For at least one of those emerging targets - the hemopoietic cells that accumulate in murine lungs after allergen challenge of the sensitized airways - the pattern of response to glucocorticoids, which have obvious clinical relevance, differs strikingly from that of the corresponding cells in bone-marrow. Such findings suggest that the issue of the role of hemopoietic cells in allergy also has an unconventional answer, as the cells themselves differ from those found in conventional sites of hemopoiesis. In this context, novel targets and avenues for therapeutic intervention are certainly waiting for the right questions to be posed, and for the right experiments to be designed. Hopefully, this Hot topic issue will provide the reader with an appropriate perspective on this exciting field, and invite new questions and experiments. For attempting that, I am deeply indebted to our contributors, who represent some of the most active groups in this field.

Recent research from many laboratories highlighted important connections between hemopoiesis and allergy / asthma. Hemopoiesis in an allergic inflammation site differs greatly from steady-state (homeostatic) hemopoiesis in the bone-marrow, due to differences in the hemopoietic factors present, as well as on their targets. One major aspect concerns the role of GM-CSF, which seems unnecessary for steady-state hemopoiesis in the absence of infection, but plays a central role in the immunobiology of the lungs, especially in the instructive phase of imunity, by its ability to influence dendritic cell differentiation and function. Allergens, alone or in combination with other factors, can induce GM-CSF production in the airways, and therefore bypass the requirement for microbial products in the activation of dendritic cells. Hemopoietic progenitors and dendritic cell precursors recruited to the lung provide additional potential targets for GM-CSF. Stem Cell Factor also plays a major role, by acting on mast cells to promote their maturation and functional activation, and on additional cell types from the lung to promote allergic inflammation, in concert with IgE antibodies and a variety of chemokines. Hemopoietic cells isolated from bone-marrow, blood and allergic lung may differ in their responses to hemopoietic factors and drugs. This is changing our perception of the effects of glucocorticoids on hemopoiesis, and especially on eosinophil differentiation. Manipulation of the process of granulocyte (eosinophil and neutrophil) apoptosis, as well as engineering modified versions of hemopoietic cytokines, such as IL-5, are current approaches to developing valuable tools for intervention in the context of hemopoiesis in allergy.

Eosinophilic infiltration is a cardinal feature of allergic inflammation; based upon its biological actions, the eosinophil has assumed the role as the principal inflammatory cell in asthma. In assessing the mechanisms by which eosinophils are recruited to sites of inflammation, a sizeable body of evidence exists supporting the proposal that expansion of hemopoietic compartments in the bone marrow stimulates an increased turnover and traffic of mature eosinophils to the site of allergic inflammation. In addition, recent findings point to the possible egress and traffic of primitive progenitor cells to the site of inflammation where in-situ differentiation may provide a continued supply of proinflammatory cells. In the present article, we will review the evidence for these findings, and discuss the rationale for targeting hemopoiesis and migrational pathways of hemopoietic cells in the treatment of allergic disease. In this context, we will discuss the effect of corticosteroid treatment on hemopoietic mechanisms; the effects of therapies that inhibit the actions of cysteinyl leukotrienes (CysLTs); the effects of in vivo blockade of the eosinophil-active cytokine, interleukin (IL)-5; and, the effects of antihistamines on hemopoiesis. In addition, we will address the potential role that small molecular weight chemokine receptor antagonists may play in modulating progenitor cell trafficking to tissue sites of inflammation.

The interaction between dendritic cells (DC) and naïve T cells is the first step in the evolution of an immune response, either tolerogenic or inflammatory. Therefore, the status of DC residing at mucosal sites, such as the airway, has a definitive impact on the character of the ensuing immune response. In the absence of pathogenic stimulation, DC serve to regulate immunological homeostasis in the lung; the generation of Th2- associated (allergic) inflammatory responses, which are directed at presumably innocuous antigens, represent a deviation from normal DC function. The dysregulation of DC phenotype leading to the development of allergy might be programmed by genetic pedigree, or might be induced by factors released in the airway. One potential candidate, GM-CSF, is abundant in the allergic airway and can condition DC to propagate Th2 responses. Moreover, that allergens, alone or in combination with other factors, can spontaneously induce GM-CSF production in the airway thus present a compelling etiological argument for the role of GM-CSF in allergic sensitization. The interplay between DC and mediators present in the allergic airway is likely critical to the establishment of allergic airway inflammation. Understanding these interactions may, therefore, afford insight into prospective therapeutic interventions to circumvent, and even reverse the allergic diathesis.

Human mast cells (MCs) and basophils play a key role in the pathogenesis of allergic disorders, not only by producing inflammatory and fibrogenic mediators, but also by directly and indirectly secreting various cytokines and chemokines. Although mast cells and basophils have differences in many properties, recent evidence suggests that human MCs and basophils may be derived from a common progenitor, and their contents and phenotypes may be reversibly altered in a variety of allergic disorders. The study of FcεRI signalling of mast cell and basophils offers new opportunities for therapeutic interventions based on the specific inhibition of the earliest events in allergic diseases. This article reviews the origin, differentiation, morphology and phenotypic properties of MCs and basophils, focussing particularly on the possible pathogenic role of MCs and basophils in allergy and biochemical targets for therapeutic interventions in allergic diseases.

Allergic diseases like atopic rhinitis, bronchial asthma, and urticaria are prevalent and on the rise. Mast cells are known to play a central role in the immediate phase reaction of allergic diseases through the IgE-mediated release of a variety of chemical mediators like histamine, leukotrienes, and prostaglandins. On the other hand, T lymphocytes, basophils and eosinophils are thought to be responsible in inducing the late phase response. Yet, recent studies show that the mast cell cannot be simplistically assigned a role in the immediate phase allergic response, and that this cell plays a crucial role in ongoing allergic inflammation, including the development of hyper-responsiveness. In the present article, the author will try to discuss the integrated roles of mast cells in IgEmediated allergic inflammation with specific emphasis on the roles of mast cell-IgE networking and mast cellstructural cell interactions in the late phase allergic response and chronic allergic inflammation.

We review evidence that Stem Cell Factor (SCF) plays an important role in the pathophysiology of asthma. SCF is produced by a wide variety of cells present in asthmatic lung, including mast cells and eosinophils. Its receptor, c-kit, is broadly expressed on mature mast cells and eosinophils. SCF promotes recruitment of mast cell progenitors into tissues, as well as their local maturation and activation. It also promotes eosinophil survival, maturation and functional activation. SCF enhances IgE-dependent release of mediators from mast cells, including histamine, leukotrienes, cytokines (TNF-α, IL-5, GM-CSF) and chemokines (RANTES / CCL5, MCP-1 / CCL2, TARC / CCL17 e MDC / CCL22); it is required for IL-4 production in mast cells. SCF, acting in concert with IgE, also upregulates the expression and function of CC chemokine receptors in mast cells. Structural and resident airway cells express increased levels of SCF in the bronchus of asthmatic patients. In a murine model of asthma, allergen exposure increased production of SCF by epithelial cells and alveolar macrophages, which was transient and paralleled by histamine release. SCF induced longlived airway hyperreactivity, which was prevented by local neutralization of SCF, as well as by inhibitors of the production or activity of cysteinyl-leukotrienes. Together, these observations suggest that SCF has an important role in asthma.

Interleukin 5 (IL-5) is the key cytokine in an eosinophil's life span: it supports eosinophilopoiesis and eosinophil differentiation, contributes to eosinophil migration, tissue localisation and function, and prevents eosinophil apoptosis. Given the likely role of eosinophils in chronic inflammatory diseases, a lot of research over the past decade was aimed at antagonising IL-5 function. It appears from recent studies that, although this can easily be achieved in vitro, blocking IL-5 function in vivo is much more difficult than originally anticipated. Here, we review the current status of IL-5 and IL-5 receptor research, with emphasis on strategies to interfere with IL-5 function.

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 α4 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.

It has become apparent that the resolution of inflammation depends on the removal of unwanted inflammatory cells, a process governed by physiological apoptosis and non-inflammatory clearance of apoptotic cells. Granulocytes are central to many of the pathophysiological consequences of uncontrolled inflammatory reactions. Hemopoietic factors and cytokines play a critical role in regulating the longevity of these cells in vitro and in vivo. Here we review the progress that has been made in the understanding of granulocyte apoptosis and the implications for immunotherapy and pharmacological strategies in the treatment of allergic inflammatory diseases for therapeutic gain.