PERSPECTIVE
Allergic Networks Regulating Eosinophilia

Paul S. Foster

Division of Biochemistry and Molecular Biology, John Curtin School of Medical Research, Australian National University, Canberra, Australia

Although asthma is a disease of complex etiology, it is becoming increasingly apparent that inflammation of the airway mucosa is a major factor predisposing to the clinical manifestations of this disease (1). The localization and activation of specific inflammatory cells within the lung correlates with the temporal phases of airway obstruction and enhanced bronchial responsiveness to spasmogenic stimuli. In particular, immunoglobulin (Ig) E-dependent activation of mast cells and CD4⁺ T-helper type 2 (Th2) cell-regulated eosinophilia are thought to be key mediators of the early- and late-phase responses of allergic asthma, respectively (1). Th2 cells and eosinophilia are also predominant features of inflammatory infiltrates during exacerbations of nonallergic asthma (6). Notably, both clinical and experimental observations show a strong correlation between the presence of eosinophils and their products in the airways, disease severity, and the development of airway hyperreactivity (4, 5). Although there is a strong correlation between eosinophilic inflammation of the bronchial mucosa and disease severity, the specific pathophysiologic mechanisms that predispose to the clinical manifestations of asthma have not been fully delineated.

Recently, murine models of allergic lung disease have been employed in attempts to provide insights into the complex inflammatory processes of the asthmatic airways. Although these models are only representative of the immunopathologic processes underlying asthma, they have provided us with an important tool to help identify the potential contribution of individual inflammatory molecules and cells to specific pathophysiologic processes that are hallmarks of this disorder. Notably, these models have provided corroborative evidence of the central importance of Th2-cells and -cytokines and eosinophilia to the etiology of asthma (7). They have also identified the importance of specific chemokines and adhesion systems for leukocyte migration to the allergic lung (10, 11).

Collectively, murine models of asthma have demonstrated that inflammation of the airways plays a central role in disease pathogenesis. Furthermore, like the human condition, pathogenic mechanisms are complex with multiple pathways regulating the development of the asthma phenotype (11). Notably, allergic disease of the lung in mouse models occurs independently of the archetypal Th2-cell differentiation factor, interleukin (IL)-4, IgE, B cells, and mast cells, suggesting the existence of compensatory pathways (8, 9, 16, 17, 20, 24). In the absence of these key regulators of allergic disease, a residual Th2-driven airways eosinophilia is a predominant feature of the inflammatory response after allergen provocation (12, 16, 20, 25). Although the recruitment of eosinophils to the airways is a central feature of all mouse models of asthma, and although this cell has been linked to the development of the asthma phenotype, the contribution of this granulocyte to the mechanisms that predispose to altered airway function remains controversial. Notably, eosinophilia has been associated and dissociated from the induction of airway hyperreactivity (7, 12, 20, 22, 25, 26). The strain of mouse, route of antigen sensitization, and frequency of airway provocation may directly influence distinct spatial and temporal aspects of the inflammatory response that regulates eosinophil-induced airway hyperreactivity (7, 17). Furthermore, the ability of the eosinophil to regulate allergic disease will depend on the allergen inhalation model providing a number of critical features: the correct microenvironment for eosinophil activation, the recruitment of a critical number of cells to the lung, and localization to the bronchial mucosa.

In this issue of the American Journal of Respiratory Cell and Molecular Biology, two investigations highlight the complexities of the inflammatory mechanisms underlying the regulation of airway eosinophilia and the subsequent participation of this granulocyte in the mechanisms leading to airway hyperreactivity. Hamelmann and colleagues (46) show that the use of different sensitization and aeroallergen challenge protocols influences the selection of T-cell repertoires and the subsequent mechanisms that regulate eosinophil-induced airway hyperreactivity. Inman and colleagues (47) provide evidence that eosinophil-progenitor cells expand in the bone marrow in response to allergic signals in the lung and that this response directly correlates to the induction of airway hyperreactivity. These investigations also support the concept that eosinophil-progenitor cells are mobile and may be recruited to the airways where they participate in the development of airway hyperreactivity. Furthermore, they demonstrate distinct spatiotemporal coordination between tissue eosinophilia and the development of airway hyperreactivity after allergen inhalation.

Regulation of Eosinophilia by CD4⁺ and CD8⁺ T cells

Recently, investigations by Hamelmann and colleagues ([18], and in this issue [46]) have elegantly shown how sensitization and aeroallergen challenge protocols can influence the immunologic milieu of the lung and the subsequent participation of the eosinophil in the mechanisms regulating airway hyperreactivity. In the first investigation, sensitization of wild-type or B-cell-deficient mice exclusively via the delivery of antigen to the airways results in eosinophilia and local production of IL-5 from T cells (18). However, enhanced airway reactivity to electrical field stimulation was only observed in wild-type mice. Notably, passive sensitization of B-cell-deficient mice with antiovalbumin (OVA) IgE antibody (intravenous administration) during the course of allergen exposure completely restored the development of airway hyperreactivity (18). However, in this model, airway hyperreactivity has been previously shown to be dependent on IL-5-regulated eosinophilia. Thus, neither B cells nor IgE was necessary for the induction of Th2-cytokine responses or eosinophilia. However, IgE was required as a second signal in addition to eosinophilia for the development of enhanced airway hyperreactivity. By contrast, intraperitoneal sensitization with antigen/alum followed by repeated exposure of the airways to antigen resulted in enhanced airway reactivity (measured by electrical field stimulation and plethysmography) in both wild-type and B-cell-deficient mice (46). Furthermore, these responses were dependent on IL-5- regulated eosinophilia. Thus, solely IL-5 was required for eosinophil infiltration and the development of airway hyperreactivity after systemic sensitization with antigen and subsequent aeroallergen challenge. Although these results highlight that the use of different sensitization and aeroallergen challenge protocols can influence the mechanisms that regulate eosinophil-induced airway hyperreactivity, the question remains of why this is the case.

A number of cells and molecules contribute to the mechanisms underlying the regulation of airway hyperreactivity in mice; however, only CD4⁺ T cells have been shown to exclusively regulate disease pathogenesis in models based on systemic sensitization and subsequent aeroallergen challenge (17, 27). Treatment of mice with anti-CD4 monoclonal antibodies (mAbs) during antigen priming or before inhalation completely abrogates the development of allergic disease in the airways. By contrast, CD8⁺ T cells play a critical role in the mechanism underlying the development of enhanced airway hyperreactivity in mice exclusively sensitized by the lung. Depletion of CD8⁺ T cells before antigen exposure to the airways attenuates airway hyperreactivity, the recruitment of eosinophils to the lung, and IL-5 production from T cells. Notably, in this model, CD8⁺ T cells and not CD4⁺ T cells were the major source of IL-5 in peribronchial lymph nodes. However, the production of IgE was not dependent on CD8⁺ T cells, implying an associated role for CD4⁺ Th2 cells and IL-4 in this model. Thus, the phenotypic expression of airway hyperreactivity in models of direct antigen inhalation appears to be dependent on the interplay between IgE, CD8⁺ T cells, and IL-5-regulated eosinophilia. In contrast, neither CD8⁺ cells nor IgE play obligatory roles in allergic lung models induced by systemic sensitization. Recently, CD8⁺ T cells have also been shown to play a critical role in the induction of IL-5-regulated eosinophilia, which underlies airway hyperreactivity in mouse models of respiratory syncytial virus (21). Thus, a number of T-cell pathways regulate eosinophilia, and under some conditions, these pathways may operate in parallel (17). Furthermore, IgE may play a key role in the mechanisms of eosinophil-induced airway hyperreactivity in some circumstances, whereas alternative pathways may be more dominant in others (12, 13, 17, 20). The mechanisms that control the relative contribution of various pathways to the induction of airway hyperreactivity have yet to be eludicated. However, these mechanisms are likely to be regulated by the differential activation and selection of the T-cell repertoire in response to the model antigen and the modality employed for sensitization and subsequent induction of allergic disease in the lung.

Do Mobile Eosinophil Progenitors Contribute to Eosinophilia in the Allergic Lung?

In response to inflammatory signals in the lung, eosinopoiesis occurs in the bone marrow, and mature eosinophils migrate from this compartment via the blood to the bronchial mucosa, where they receive specific signals to release a range of proinflammatory mediators that drive pathogenesis (1, 3). However, evidence is also accumulating for an extramedullary role of eosinophil progenitor cells in the pathogenesis of allergic disease (5, 28). An emerging hypothesis is that communication between the lung and bone marrow compartments in response to allergen provocation upregulates the production of eosinophil progenitors in the bone marrow. These IL-5-responsive cells then undergo differentiation in the bone marrow or migrate to the allergic lung. Cytokines elaborated from resident inflammatory and airway cells then locally drive differentiation of these lineage-committed progenitor cells to mature effector cells. Thus, two mechanisms may operate to promote eosinophilia during allergic response: one localized to the bone marrow compartment, and the other at the site of inflammation.

A role for eosinophil progenitors in the allergic inflammatory cascade is partly based on the observations that these cells are elevated in the blood of atopic individuals after seasonal exposure to allergens, and that circulating numbers often correlate with the exacerbation and resolution of clinical asthma (31). Furthermore, allergen challenge of atopic asthmatics results in the specific upregulation of eosinophil progenitor cells (CD34⁺, CD45⁺, IL-5 receptor-alpha-chain⁺) in the bone marrow and blood (36, 37). Investigations in canine and mouse models of allergic lung disease have also provided experimental evidence for a role of bone-marrow myeloid progenitors in allergen-induced airway hyperreactivity (38). In particular, allergen challenge of sensitized mice results in increased numbers of mature eosinophils in the bone marrow and myeloid progenitor cells that are responsive to IL-5 and IL-3 (38, 42).

In this issue, Inman and colleagues (47) have extended these observation by developing an allergen challenge model in mice whereby they could correlate the development of airway hyperreactivity with the recruitment of eosinophils to the airways and the expansion of IL-5- responsive eosinophil-progenitor cells in the bone marrow. Importantly, their findings demonstrate that eosinopoiesis in response to allergen provocation of the airways is regulated by the expansion of an eosinophil-progenitor population in the bone marrow and not solely by increased kinetics of division/maturation of an existing pool. Furthermore, the development of the eosinophil-progenitor population in the bone marrow temporally correlates with the induction of airway hyperreactivity to cholinergic stimuli. These observations support investigations in patients with asthma where allergen-induced bronchial hyperreactivity was directly associated with increased numbers of bone-marrow eosinophil and basophil colony-forming units (38, 42). Notably, the recruitment of lymphocytes and eosinophils into the bronchial alveolar lavage fluid (BALF) was dissociated from the development of airway hyperreactivity (see subsequent discussion).

Currently, the signals regulating eosinophil-progenitor cell expansion and subsequent emigration from the bone marrow and localization to the lung are unknown. However, recent investigations in guinea pigs and mouse models of allergic lung disease suggest that IL-5 and eotaxin play key roles. Eotaxin plays integral roles in baseline homing of eosinophils to mucosal tissues and in the early phase of eosinophil recruitment to sites of allergic inflammation (5, 43). Furthermore, this chemokine regulates the mobilization of eosinophils and their progenitor cells from the bone marrow into the blood (44). By contrast, IL-5 regulates the growth, differentiation, and activation of eosinophils (5). Studies in IL-5-deficient mice also show that this cytokine plays a critical role in the expansion and the mobilization of the bone marrow eosinophil pool in response to allergen inhalation (14). Notably, the transient expression of this cytokine in the lungs of IL-5-deficient mice only restored eosinophilia in the bone marrow, blood, and lung after mice were sensitized and aeroallergen challenged, indicating that additional factors are required to amplify the IL-5 signal for eosinopoiesis and migration (14). IL-3 and granulocyte macrophage colony-stimulating factor (GM-CSF) are known to prime progenitor cells for IL-5 responsiveness (5). However, although IL-5, GM-CSF, and IL-3 all contribute to eosinopoiesis, mature eosinophils are found in the bone marrow of mice deficient in these factors or in common components of their receptor signaling systems (14, 45). Thus, in the limited number of investigations to date it would appear that IL-5 derived from the lung and cells resident in the bone marrow (CD3⁺ and CD3 cells) act in concert with as yet undefined signals derived from the site of allergen provocation to regulate eosinopoiesis.

Of particular note in the investigation by Inman and colleagues is the spatial and temporal accumulation of eosinophils in the airways with the correlates of airway hyperreactivity and eosinophil-progenitor expansion in the bone marrow. Airway hyperreactivity and increased eosinophil-progenitor colonies were only observed at 24 and 48 h postallergen inhalation. By contrast, BALF eosinophil numbers were significantly elevated at all time points, but peaked at 24 and 48 h. At 2 h, eosinophils were associated only with the perivascular regions. By 12 h, eosinophils had migrated into the parenchymal tissue adjacent to the airways but not into the epithelial or subepithelial regions. At later time points, eosinophils had localized to both the perivascular and peribronchial regions. Although speculative, these results indicate that the location and perhaps the number of eosinophils in the airways, in association with activation status, may be critical for the induction of airway hyperreactivity. It should also be noted that the recruitment of lymphocytes to the BALF mirrored that of eosinophils. Thus, these data also highlight the potential complexities of the interplay between signals elicited after allergen challenge, leukocyte recruitment to the lung, and the temporal phase for the induction of airway hyperreactivity. Indeed, the association or dissociation of a specific leukocyte with airway hyperreactivity may be critically dependent on the time of analyses after allergen inhalation.

Although a number of cytokines have been shown to play important roles in the development of eosinophils, the critical signals regulating commitment to this lineage in the bone marrow at baseline or in response to allergic stimulation have not yet been delineated. The model described by Inman and colleagues in this issue will now provide an important tool to dissect the signaling mechanisms regulating eosinophil-progenitor development in response to allergen provocation of the lung, and this model will also help to identify the role of this cell in the spatial and temporal aspects of inflammation that predispose to airway hyperreactivity.

Collectively, mouse models of asthma convincingly support the clinical paradigm that Th2-like T cells and cytokines play elemental roles in orchestrating the inflammatory response that predisposes to pathogenesis. Furthermore, they support the concept that the eosinophil plays a central role in the clinical manifestation of this disease. Characterization of the various pathways underlying T-cell-regulated eosinophilia and the elemental processes regulating eosinophil development will provide important insights into the molecular networks predisposing to asthma and will facilitate the design of novel therapeutic targets for the resolution of this disease.

	Footnotes

Address correspondence to: Dr. Paul S. Foster, Associate Professor, Leukocyte Signalling and Regulation Laboratory, Division of Biochemistry and Molecular Biology, John Curtin School of Medical Research, Australian National University, ACTON ACT 0200. E-mail: Paul.Foster{at}anu.edu.au

(Received in original form August 16, 1999).

Acknowledgments: The author would like to thank Drs. K. I. Matthaei and D. Webb and Ms. J. Young for their input into this manuscript.

	References

1. Bochner, B. S., B. J. Undem, and L. M. Lichtenstein. 1994. Immunologial aspects of allergic asthma. Annu. Rev. Immunol. 12: 295-335 [Medline].

2. Sears, M. R., B. Burrows, E. M. Flannery, G. P. Herbison, C. J. Hewitt, and M. D. Holdaway. 1991. Relation between airway responsiveness and serum IgE in children with asthma and in apparently normal children. N. Engl. J. Med. 325: 1067-1071 [Abstract].

3. Seminario, M. C., and G. J. Gleich. 1994. The role of eosinophils in the pathogenesis of asthma. Curr. Opin. Immunol. 6: 860-864 [Medline].

4. De Monchy, J. G., H. F. Kauffman, P. Venge, G. H. Koeter, H. M. Jansen, H. J. Sluiter, and K. De Vries. 1985. Bronchoalveolar eosinophilia during allergen-induced late asthmatic reactions. Am. Rev. Respir. Dis. 131: 373-376 [Medline].

5. Rothenberg, M. E.. 1998. Eosinophilia. N. Engl. J. Med. 338: 1592-1600 [Free Full Text].

6. Walker, C., E. Bode, L. Boer, T. T. Hansel, K. Blaser, and J. C. Virchow Jr.. 1992. Allergic and nonallergic asthmatics have distinct patterns of T-cell activation and cytokine production in peripheral blood and bronchoalveolar lavage. Am. Rev. Respir. Dis. 146: 109-115 [Medline].

7. Drazen, J. M., J. P. Arm, and K. F. Austen. 1996. Sorting out the cytokines of asthma [comment]. J. Exp. Med. 183: 1-5 [Free Full Text].

8. Gleich, G. J., and H. Kita. 1997. Bronchial asthma: lessons from murine models [comment]. Proc. Natl. Acad. Sci. USA 94: 2101-2102 [Free Full Text].

9. Galli, S. J.. 1997. Complexity and redundancy in the pathogenesis of asthma: reassessing the roles of mast cells and T cells. J. Exp. Med. 186: 343-347 [Free Full Text].

10. Kita, H., and G. J. Gleich. 1996. Chemokines active on eosinophils: potential roles in allergic inflammation [comment]. J. Exp. Med. 183: 2421-2426 [Free Full Text].

11. Gonzalo, J. A., C. M. Lloyd, D. Wen, J. P. Albar, T. N. Wells, A. Proudfoot, A. C. Martinez, M. Dorf, T. Bjerke, A. J. Coyle, and J. C. Gutierrez-Ramos. 1998. The coordinated action of CC chemokines in the lung orchestrates allergic inflammation and airway hyperresponsiveness. J. Exp. Med. 188: 157-167 [Abstract/Free Full Text].

12. Corry, D. B., H. G. Folkesson, M. L. Warnock, D. J. Erle, M. A. Matthay, J. P. Wiener, Kronish, and R. M. Locksley. 1996. Interleukin 4, but not interleukin 5 or eosinophils, is required in a murine model of acute airway hyperreactivity [see comments]. J. Exp. Med. 183: 019-117 .

13. Eum, S. Y., S. Haile, J. Lefort, M. Huerre, and B. B. Vargaftig. 1995. Eosinophil recruitment into the respiratory epithelium following antigenic challenge in hyper-IgE mice is accompanied by interleukin 5-dependent bronchial hyperresponsiveness. Proc. Natl. Acad. Sci. USA 92: 12290-12294 [Abstract/Free Full Text].

14. Foster, P. S., S. P. Hogan, A. J. Ramsay, K. J. Matthaei, and I. G. Young. 1996. Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model [see comments]. J. Exp. Med. 183: 195-201 [Abstract/Free Full Text].

15. Grunig, G., M. Warnock, A. E. Wakil, R. Venkayya, F. Brombacher, D. M. Rennick, D. Sheppard, M. Mohrs, D. D. Donaldson, R. M. Locksley, and D. B. Corry. 1998. Requirement for IL-13 independently of IL-4 in experimental asthma [see comments]. Science 282: 2261-2263 [Abstract/Free Full Text].

16. Hogan, S. P., A. Mould, H. Kikutani, A. J. Ramsay, and P. S. Foster. 1997. Aeroallergen-induced eosinophilic inflammation, lung damage, and airways hyperreactivity in mice can occur independently of IL-4 and allergen-specific immunoglobulins. J. Clin. Invest. 99: 1329-1339 [Medline].

17. Hogan, S. P., K. I. Matthaei, J. M. Young, A. Koskinen, I. G. Young, and P. S. Foster. 1998. A novel T cell-regulated mechanism modulating allergen-induced airways hyperreactivity in BALB/c mice independently of IL-4 and IL-5. J. Immunol. 161: 1501-1509 [Abstract/Free Full Text].

18. Hamelmann, E., A. Oshiba, J. Paluh, K. Bradley, J. Loader, T. A. Potter, G. L. Larsen, and E. W. Gelfand. 1996. Requirement for CD8⁺ T cells in the development of airway hyperresponsiveness in a murine model of airway sensitization. J. Exp. Med. 183: 1719-1729 [Abstract/Free Full Text].

19. Korsgren, M., C. G. Persson, F. Sundler, T. Bjerke, T. Hansson, B. J. Chambers, S. Hong, L. Van Kaer, H. G. Ljunggren, and O. Korsgren. 1999. Natural killer cells determine development of allergen-induced eosinophilic airway inflammation in mice. J. Exp. Med. 189: 553-562 [Abstract/Free Full Text].

20. Mehlhop, P. D., M. van de Rijn, A. B. Goldberg, J. P. Brewer, V. P. Kurup, T. R. Martin, and H. C. Oettgen. 1997. Allergen-induced bronchial hyperreactivity and eosinophilic inflammation occur in the absence of IgE in a mouse model of asthma [see comments]. Proc. Natl. Acad. Sci. USA 94: 1344-1349 [Abstract/Free Full Text].

21. Schwarze, J., G. Cieslewicz, A. Joetham, T. Ikemura, E. Hamelmann, and E. W. Gelfand. 1999. CD8 T cells are essential in the development of respiratory syncytial virus-induced lung eosinophilia and airway hyperresponsiveness. J. Immunol. 162: 4207-4211 [Abstract/Free Full Text].

22. Wills-Karp, M., J. Luyimbazi, X. Xu, B. Schofield, T. Y. Neben, C. L. Karp, and D. D. Donaldson. 1998. Interleukin-13: central mediator of allergic asthma [see comments]. Science 282: 2258-2261 [Abstract/Free Full Text].

23. Zhu, Z., R. J. Homer, Z. Wang, Q. Chen, G. P. Geba, J. Wang, Y. Zhang, and J. A. Elias. 1999. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J. Clin. Invest. 103: 779-788 [Medline].

24. Takeda, K., E. Hamelmann, A. Joetham, L. D. Shultz, G. L. Larsen, C. G. Irvin, and E. W. Gelfand. 1997. Development of eosinophilic airway inflammation and airway hyperresponsiveness in mast cell-deficient mice. J. Exp. Med. 186: 449-454 [Abstract/Free Full Text].

25. Hamelmann, E., A. T. Vella, A. Oshiba, J. W. Kappler, P. Marrack, and E. W. Gelfand. 1997. Allergic airway sensitization induces T cell activation but not airway hyperresponsiveness in B cell-deficient mice. Proc. Natl. Acad. Sci. USA 94: 1350-1355 [Abstract/Free Full Text].

26. Henderson, W. R. Jr., D. B. Lewis, R. K. Albert, Y. Zhang, W. J. Lamm, G. K. Chiang, F. Jones, P. Eriksen, Y. T. Tien, M. Jonas, and E. Y. Chi. 1996. The importance of leukotrienes in airway inflammation in a mouse model of asthma. J. Exp. Med. 184: 1483-1494 [Abstract/Free Full Text].

27. Gavett, S. H., X. Chen, F. Finkelman, and M. Wills-Karp. 1994. Depletion of murine CD4+ T lymphocytes prevents antigen-induced airway hyperreactivity and pulmonary eosinophilia. Am. J. Respir. Cell Mol. Biol. 10: 587-593 [Abstract].

28. Denburg, J. A., M. D. Inman, L. Wood, R. Ellis, R. Sehmi, M. Dahlback, and P. O'Byrne. 1997. Bone marrow progenitors in allergic airways diseases: studies in canine and human models. Int. Arch. Allergy Immunol. 113: 181-183 [Medline].

29. Denburg, J. A., L. Wood, G. Gauvreau, R. Sehmi, M. D. Inman, and P. M. O'Byrne. 1997. Bone marrow contribution to eosinophilic inflammation. Mem. Inst. Oswaldo Cruz. 92: 33-35 .

30. Denburg, J. A.. 1999. Bone marrow in atopy and asthma: hematopoietic mechanisms in allergic inflammation. Immunol. Today 20: 111-113 [Medline].

31. Otsuka, H., J. Denburg, J. Dolovich, D. Hitch, P. Lapp, R. S. Rajan, J. Bienenstock, and D. Befus. 1985. Heterogeneity of metachromatic cells in the human nose: significance of mucosal mast cells. J. Allergy Clin. Immunol. 76: 695-702 [Medline].

32. Otsuka, H., J. Dolovich, D. Befus, J. Bienenstock, and J. Denburg. 1986. Peripheral blood basophils, basophil progenitors, and nasal metachromatic cells in allergic rhinitis. Am. Rev. Respir. Dis. 133: 757-762 [Medline].

33. Wood, L. J., M. D. Inman, R. M. Watson, R. Foley, J. A. Denburg, and P. M. O'Byrne. 1998. Changes in bone marrow inflammatory cell progenitors after inhaled allergen in asthmatic subjects. Am. J. Respir. Crit. Care Med. 157: 99-105 [Abstract/Free Full Text].

34. Gibson, P. G., J. Dolovich, A. Girgis-Gabardo, M. M. Morris, M. Anderson, F. E. Hargreave, and J. A. Denburg. 1990. The inflammatory response in asthma exacerbation: changes in circulating eosinophils, basophils and their progenitors. Clin. Exp. Allergy 20: 661-668 [Medline].

35. Gibson, P. G., P. J. Manning, P. M. O'Byrne, A. Girgis-Garbardo, J. Dolovich, J. A. Denburg, and F. E. Hargreave. 1991. Allergen-induced asthmatic responses: relationship between increases in airway responsiveness and increases in circulating eosinophils, basophils, and their progenitors. Am. Rev. Respir. Dis. 143: 331-335 [Medline].

36. Denburg, J. A., R. Sehmi, J. Upham, L. Wood, G. Gauvreau, and P. O'Byrne. 1999. Regulation of IL-5 and IL-5 receptor expression in the bone marrow of allergic asthmatics. Int. Arch. Allergy Immunol. 118: 101-103 [Medline].

37. Sehmi, R., L. J. Wood, R. Watson, R. Foley, Q. Hamid, P. M. O'Byrne, and J. A. Denburg. 1997. Allergen-induced increases in IL-5 receptor alpha-subunit expression on bone marrow-derived CD34+ cells from asthmatic subjects: a novel marker of progenitor cell commitment towards eosinophilic differentiation. J. Clin. Invest. 100: 2466-2475 [Medline].

38. Ohkawara, Y., X. F. Lei, M. R. Stampfli, J. S. Marshall, Z. Xing, and M. Jordana. 1997. Cytokine and eosinophil responses in the lung, peripheral blood, and bone marrow compartments in a murine model of allergen- induced airways inflammation [see comments]. Am. J. Respir. Cell Mol. Biol. 16: 510-520 [Abstract].

39. Inman, M. D., J. A. Denburg, R. Ellis, M. Dahlback, and P. M. O'Byrne. 1996. Allergen-induced increase in bone marrow progenitors in airway hyperresponsive dogs: regulation by a serum hemopoietic factor. Am. J. Respir. Cell Mol. Biol. 15: 305-311 [Abstract].

40. Woolley, M. J., J. A. Denburg, R. Ellis, M. Dahlback, and P. M. O'Byrne. 1994. Allergen-induced changes in bone marrow progenitors and airway responsiveness in dogs and the effect of inhaled budesonide on these parameters. Am. J. Respir. Cell Mol. Biol. 11: 600-606 [Abstract].

41. Wood, L. J., M. D. Inman, J. A. Denburg, and P. M. O'Byrne. 1998. Allergen challenge increases cell traffic between bone marrow and lung. Am. J. Respir. Cell Mol. Biol. 18: 759-767 [Abstract/Free Full Text].

42. Gaspar Elsas, M. I., D. Joseph, P. X. Elsas, and B. B. Vargaftig. 1997. Rapid increase in bone-marrow eosinophil production and responses to eosinopoietic interleukins triggered by intranasal allergen challenge. Am. J. Respir. Cell Mol. Biol. 17: 404-413 [Abstract/Free Full Text].

43. Matthews, A. N., D. S. Friend, N. Zimmermann, M. N. Sarafi, A. D. Luster, E. Pearlman, S. E. Wert, and M. E. Rothenberg. 1998. Eotaxin is required for the baseline level of tissue eosinophils. Proc. Natl. Acad. Sci. USA 95: 6273-6278 [Abstract/Free Full Text].

44. Palframan, R. T., P. D. Collins, T. J. Williams, and S. M. Rankin. 1998. Eotaxin induces a rapid release of eosinophils and their progenitors from the bone marrow. Blood 91: 2240-2248 [Abstract/Free Full Text].

45. Nishinakamura, R., A. Miyajima, P. J. Mee, V. L. Tybulewicz, and R. Murray. 1996. Hematopoiesis in mice lacking the entire granulocyte-macrophage colony-stimulating factor/interleukin-3/interleukin-5 functions. Blood 88: 2458-2464 [Abstract/Free Full Text].

46. Hamelmann, E., K. Takeda, J. Schwarze, A. T. Vella, C. G. Irvin, and E. W. Gelfand. 1999. Development of eosinophilic airway inflammation and airway hyperresponsiveness requires interleukin-5 but not immunoglobulin E or B lymphocytes. Am. J. Respir. Cell Mol. Biol. 21: 480-489 [Abstract/Free Full Text].

47. Inman, M. D., R. Ellis, J. Wattie, J. A. Denburg, and P. M. O'Byrne. 1999. Allergin-induced increase in airway responsiveness, airway eosinophilia, and bone-marrow eosinophil progenitors in mice. Am. J. Respir. Cell Mol. Biol. 21: 473-479 [Abstract/Free Full Text].