A topic and atopyrelated diseases such as asthma, allergic rhinitis, and atopic dermatitis have until now primarily been conceived as occurring in specific local tissues, for example the lung, nose, and skin, respectively. Recently, however, the notion of the systemic nature of allergy has been proposed, based on numerous clinical, neurophysiologic, and epidemiologic findings. Although the exact nature of these relationships is still not fully understood, an important mechanism to consider is the active participation of the bone marrow (BM) and related systemic hemopoietic events in the development and maintenance of local tissue allergic inflammation.
In response to allergen provocation, a systemic response is activated in subjects with allergic diseases that involves the initiation of BM production of specific inflammatory cell (eosinophil/basophil [Eo/B]) progenitors, leading to early initiation of Eo/B differentiation and release of both progenitors and their progeny from the BM compartment; these cells are then typically recruited to the respiratory mucosa and other tissues in atopic individuals. Understanding the cellular and molecular signaling involved in these systemic responses, ie, between the tissue (especially the airways) and the BM, may open up new avenues of therapy for allergic inflammation, as well help in the optimization of dosage and routes of therapy.
This review will examine how the BM supplies hemopoietic progenitors to sites of allergic inflammation and what modulates these progenitors physiologically and, potentially, therapeutically. Evidence concerning the “systemic effects” of current and experimental allergy therapies will also be discussed.
Hemopoietic Processes in Allergic Inflammation
In adults, hemopoietic stem-cell differentiation and maturation have traditionally been thought to be restricted to the BM microenvironment. However, a novel view has emerged in recent years according to which at least some hemopoietic (and nonhemopoi-etic) stem cells present in adult tissue may be recruited from the BM, through the peripheral circulation, into tissues, becoming part of a regenerative and/or inflammatory process at these “distal” sites. This process has been referred to as the plasticity of stem cells. More specifically, hemopoietic progenitor cells have the potential not only to give rise to mature cells within the BM compartment that can then egress into the circulation, but may also egress from the BM as immature progenitors, and home to various organs and tissues under the orchestrated control of specific chemokines and cytokines. Once within the tissue, the fate of these primitive hemopoietic progenitor cells is determined by locally elaborated growth factors that permit a process termed “in situ hemopoiesis.
CD34 is a stage-specific hemopoietic cell antigen that can aid in accurately enumerating progenitor cells in cord blood, peripheral blood, BM and, more recently, lung tissue and sputum, using flow cytometric methodologies. Studies in adults have shown that a circulating, common progenitor of eosinophils and basophils, measured as in vitro colony-forming units (Eo/B colony-forming units [Eo/B-CFU]), is detectable in greater numbers in the peripheral blood of asymptomatic atopic patients, compared with nonatopic control subjects; these Eo/B-CFU are responsive to activated T-(especially T-helper type 2 [Th2]) cell-derived cytokines and chemokines, and specifically to interleukin (IL)-5. Additional studies extended these findings by showing relevant fluctuations in blood and BM Eo/B-CFU in response to allergen-induced allergic inflammatory responses. The finding that, following natural allergen exposure, the numbers of circulating Eo/B-CFU are greatly reduced in symptomatic allergic rhinitis at the peak of a pollen season is an indication that during the inflammatory process, progenitor cells may home to tissue site(s) of inflammation. Previous seasonal allergic rhinitis studies found that Eo/B-CFU fell twofold to sixfold in mid-season (p < 0.02); this is equivalent to a reduction in potential mature Eo/B generation and availability in tissues of several orders of magnitude, even assuming a conservative estimate of 100 to 500 nascent Eo/B from each progenitor.
In addition, the detection of locally elaborated hemopoietic growth factors and Eo/B-CFU within nasal polyps further supports the concept of in situ hemopoiesis. This view is strengthened by the following findings:
- CD34-immunopositive/IL-5 receptor a (IL-5Ra) messenger RNA cells are detected in lung biopsy samples from atopic asthmatic patients;
- ex vivo allergen challenge of nasal explant tissue from allergic rhinitics demonstrates IL-5-driven eosinophil differentiation;
- in mouse models of allergen-induced airway eosinophilia, increased numbers of IL-5-responsive Eo/B-CFU can be grown from lung-extracted progenitors following allergen challenge, compared with saline solution challenge.
Mouse models of allergic rhinitis have highlighted the multifactorial nature of this inflammatory disease, and directly implicate the role of hemopoietic processes in allergic airways disease, specifically in allergic rhinitis and allergic asthma. The upregula-tion of myeloid progenitors in the BM after airway allergen inhalation, and their trafficking to the airways from the BM in several animal models of either upper or lower airways inflammation, have been dem-onstrated. The resultant blood, nasal, and/or pulmonary eosinophilia in these models can be blocked by antibodies to IL-5, or by deletion of the gene encoding IL-513; eotaxin is also critical in this process. Rather than demonstrating a complete ablation of the allergic inflammatory response in the nose, IL-5-deficient mice have delayed nasal symptoms and basophilic, rather than eosinophilic, inflammation within the nasal mucosa. Hemopoietic cytokine redundancy among IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor is thought to ensure adequate production of inflammatory cell progenitors even in the absence of one of these cytokines, eg, IL-5. This may partially explain the results of the effects of anti-IL-5 therapy in asthma, for which it has been shown to cause a maturational arrest of Eo/B progenitors. Likewise, as proof of concept, anti-IL-5 has now proven to be useful in managing hypereosinophilic syndrome, and may also be beneficial in clinical trials in patients with asthma with airway eosinophilia associated with poor control when corticosteroids (CS) are reduced.
These data support the concept that systemic, hemopoietic mechanisms are involved in rhinitis as well as asthma. It is quite possible that similar mechanisms contribute to eosinophilic esophagitis, atopic dermatitis, and bronchitis in patients with increased sputum eosinophils.
Phenotypic analyses of progenitor cells using CD34, together with antibodies to cytokine and chemokine receptors, has provided insight into the contribution of systemic and tissue related-hemopoietic processes in the development of allergic inflammatory responses. We have shown that, whereas upregulation of IL-5Ra on CD34 cells within the BM promotes increased eosinophilopoiesis, the upregulation of the chemokine receptor CCR3 on CD34 cells may favor increased traffic of progenitor cells from the BM to the peripheral circulation in response to eotaxin. Chemokines may therefore orchestrate the egress of progenitor cells from the BM microenvironment and the homing of progenitor cells to tissue sites of inflammation, such as the upper and lower airways. An important candidate may be stromal cell-derived factor (SDF)-1, a potent progenitor cell chemoattractant that plays a role in stem-cell homing during embryogenesis (Fig 1).
Figure 1. Systemic hemopoietic processes involving active communication among upper and lower airways tissue sites, the BM, and the bloodstream are depicted schematically, highlighting key cytokines and chemokines. Both differentiative and migratory events are critical in the participation of hemopoietic and, specifically, eosinophilopoietic progenitors in allergic diseases and asthma.