Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model.
01 Jan 1996-Journal of Experimental Medicine (Rockefeller University Press)-Vol. 183, Iss: 1, pp 195-201
TL;DR: Results indicate that IL-5 and eosinophils are central mediators in the pathogenesis of allergic lung disease.
Abstract: Airways inflammation is thought to play a central role in the pathogenesis of asthma. However, the precise role that individual inflammatory cells and mediators play in the development of airways hyperreactivity and the morphological changes of the lung during allergic pulmonary inflammation is unknown. In this investigation we have used a mouse model of allergic pulmonary inflammation and interleukin (IL) 5-deficient mice to establish the essential role of this cytokine and eosinophils in the initiation of aeroallergen-induced lung damage and the development of airways hyperreactivity. Sensitization and aerosol challenge of mice with ovalbumin results in airways eosinophilia and extensive lung damage analogous to that seen in asthma. Aeroallergen-challenged mice also display airways hyperreactivity to beta-methacholine. In IL-5-deficient mice, the eosinophilia, lung damage, and airways hyperreactivity normally resulting from aeroallergen challenge were abolished. Reconstitution of IL-5 production with recombinant vaccinia viruses engineered to express this factor completely restored aeroallergen-induced eosinophilia and airways dysfunction. These results indicate that IL-5 and eosinophils are central mediators in the pathogenesis of allergic lung disease.
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TL;DR: This article showed that IL-4 receptor α chain-dependent pathway may underlie the genetic associations of asthma with both the human 5q31 locus and the IL4 receptor and showed that selective neutralization of IL-13, a cytokine related to interleukin-4 that also binds to the α chain of the IL 4 receptor, ameliorated asthma phenotype.
Abstract: The pathogenesis of asthma reflects, in part, the activity of T cell cytokines. Murine models support participation of interleukin-4 (IL-4) and the IL-4 receptor in asthma. Selective neutralization of IL-13, a cytokine related to IL-4 that also binds to the α chain of the IL-4 receptor, ameliorated the asthma phenotype, including airway hyperresponsiveness, eosinophil recruitment, and mucus overproduction. Administration of either IL-13 or IL-4 conferred an asthma-like phenotype to nonimmunized T cell–deficient mice by an IL-4 receptor α chain–dependent pathway. This pathway may underlie the genetic associations of asthma with both the human 5q31 locus and the IL-4 receptor.
1,904 citations
TL;DR: A single dose of monoclonal antibody to IL-5 decreased blood eosinophils for up to 16 weeks and sputum eosInophils at 4 weeks, which has considerable therapeutic potential for asthma and allergy, however, the findings question the role of eos inophils in mediating the late asthmatic response and causing airway hyper-responsiveness.
1,824 citations
TL;DR: The targeted pulmonary expression of IL-13 causes a mononuclear and eosinophilic inflammatory response, mucus cell metaplasia, airway fibrosis, eotaxin production, airways obstruction, and nonspecific AHR in transgene-positive animals.
Abstract: Interleukin (IL)-13 is a pleiotropic cytokine produced in large quantities by activated CD4+ Th2 lymphocytes. To define further its potential in vivo effector functions, the Clara cell 10-kDa protein promoter was used to express IL-13 selectively in the lung, and the phenotype of the resulting transgenic mice was characterized. In contrast to transgene-negative littermates, the lungs of transgene-positive mice contained an inflammatory response around small and large airways and in the surrounding parenchyma. It was mononuclear in nature and contained significant numbers of eosinophils and enlarged and occasionally multinucleated macrophages. Airway epithelial cell hypertrophy, mucus cell metaplasia, the hyperproduction of neutral and acidic mucus, the deposition of Charcot-Leyden‐like crystals, and subepithelial airway fibrosis were also prominently noted. Eotaxin protein and mRNA were also present in large quantities in the lungs of the transgene-positive, but not the transgene-negative, mice. IL-4, IL-5, granulocyte-macrophage colony-stimulating factor, and monocyte chemoattractant protein-5 were not similarly detected. Physiological evaluations revealed significant increases in baseline airways resistance and airways hyperresponsiveness (AHR) to methacholine in transgene-positive animals. Thus, the targeted pulmonary expression of IL-13 causes a mononuclear and eosinophilic inflammatory response, mucus cell metaplasia, the deposition of Charcot-Leyden‐like crystals, airway fibrosis, eotaxin production, airways obstruction, and nonspecific AHR. IL-13 may play an important role in the pathogenesis of similar responses in asthma or other Th2-polarized tissue responses. J. Clin. Invest. 103:779-788 (1999).
1,695 citations
TL;DR: Measurement of AR to inhaled methacholine by barometric whole-body plethysmography is a valid indicator of airway hyperresponsiveness after allergic sensitization in mice, and it is shown that AR measured as Penh was associated with increased IgE production and eosinophil lung infiltration.
Abstract: To study the mechanisms and kinetics underlying the development of increased airway responsiveness (AR) after allergic sensitization, animal models have been invaluable. Using barometric whole-body plethysmography and increases in enhanced pause (Penh) as an index of airway obstruction, we measured responses to inhaled methacholine in conscious, unrestrained mice after sensitization and airway challenge with ovalbumin (OVA). Sensitized and challenged animals had significantly increased AR to aerosolized methacholine compared with control animals. AR measured as Penh was associated with increased IgE production and eosinophil lung infiltration. In a separate approach we confirmed the involvement of the lower airways in the response to aerosolized methacholine using tracheotomized mice. Increases in Penh values after methacholine challenge were also correlated with increased intrapleural pressure, measured via an esophageal tube. Lastly, mice demonstrating AR using a noninvasive technique also demonstrated ...
1,331 citations
Cites background from "Interleukin 5 deficiency abolishes ..."
...Several reports have described the roles that interleukin-4 (IL-4) (8), IL-5 (9, 10), and eosinophil lung infiltration (11, 12) play in the development of AHR in allergen-sensitized mice, but additional studies are needed to better define the kinetics and mechanisms underlying AHR....
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TL;DR: Current understanding of the pathophysiologic mechanisms by which Th2 cytokines induce airway disease, and the factors that predispose to the generation of these pathogenic cells in response to inhalation of ubiquitous aero-allergens are discussed.
Abstract: ▪ Abstract The incidence, morbidity, and mortality of asthma has increased worldwide over the last two decades. Asthma is a complex inflammatory disease of the lung characterized by variable airflow obstruction, airway hyperresponsiveness (AHR), and airway inflammation. The inflammatory response in the asthmatic lung is characterized by infiltration of the airway wall with mast cells, lymphocytes, and eosinophils. Although asthma is multifactorial in origin, the inflammatory process in the most common form of the disease (extrinsic asthma) is believed to be a result of inappropriate immune responses to common aero-allergens in genetically susceptible individuals. As such, it has been hypothesized that CD4+ T cells that produce a Th2 pattern of cytokines play a pivotal role in the pathogenesis of this disease. Through the release of cytokines such as IL-4, IL-13, and IL-5, these cells orchestrate the recruitment and activation of the primary effector cells of the allergic response, the mast cell and the eo...
1,058 citations
References
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TL;DR: Atopic asthma is associated with activation in the bronchi of the interleukin-3, 4, and 5 and GM-CSF gene cluster, a pattern compatible with predominant activation of the TH2-like T-cell population.
Abstract: Background. In atopic asthma, activated T helper lymphocytes are present in bronchial-biopsy specimens and bronchoalveolar-lavage (BAL) fluid, and their production of cytokines may be important in the pathogenesis of this disorder. Different patterns of cytokine release are characteristic of certain subgroups of T helper cells, termed TH1 and TH2, the former mediating delayed-type hypersensitivity and the latter mediating IgE synthesis and eosinophilia. The pattern of cytokine production in atopic asthma is unknown. Methods. We assessed cells obtained by BAL in subjects with mild atopic asthma and in normal control subjects for the expression of messenger RNA (mRNA) for interleukin-2, 3, 4, and 5, granulocytemacrophage colony-stimulating factor (GM-CSF), and interferon gamma by in situ hybridization with 32P-labeled complementary RNA. Localization of mRNA to BAL T cells was assessed by simultaneous in situ hybridization and immunofluorescence and by in situ hybridization after immunomagnetic enrichment or...
2,898 citations
"Interleukin 5 deficiency abolishes ..." refers background in this paper
...The cellular composition of the inflammatory infiltrate in the lung is characterized by increased numbers of activated neutrophils, mast cells, eosinophils, and monocytes, and the recruitment and/or activation of these cells appears to be controlled by the secretion of cytokines and chemotactic agents from antigenstimulated T lymphocytes (4-8)....
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...Furthermore, activated CD4 + Th2-type cells, which can produce IL-5 and several other cytokines, are activated in a greater proportion in asthmatic individuals (6-8, 13)....
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TL;DR: It is concluded that allergic asthma is accompanied by extensive inflammatory changes in the airways, even in mild clinical and subclinical disease.
Abstract: We have undertaken detailed cellular and ultrastructural examination of bronchial biopsies and bronchial lavage fluid from allergic asthmatic patients in order to determine the nature and degree of the inflammatory processes in mild allergic asthma. Eight atopic asthmatic patients (mean PC20 histamine, 0.90 mg/ml) and four nonasthmatic control subjects underwent fiberoptic bronchoscopy. All asthmatic subjects were clinically stable for 2 wk prior to bronchoscopy and required either no treatment or inhaled albuterol alone. A single 50-ml bronchial wash was undertaken, followed by endobronchial biopsy of subcarinae. These procedures were repeated in the asthmatic subjects 18 h after bronchial provocation with allergen or methacholine. Subsequently, all subjects underwent bronchial reactivity testing with inhaled histamine. The clinical and physiologic data were not revealed to the pathologist interpreting the specimens. The asthmatic subjects shed a significantly greater number of epithelial cells into the ...
1,142 citations
"Interleukin 5 deficiency abolishes ..." refers background or methods in this paper
...Clinical investigations show a correlation between the presence of activated inflammatory cells, histological changes to pulmonary tissue, and the development of airways hyperreactivity (2-5)....
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...Furthermore, evidence for the role o f eosinophils in the development of airways hyperreactivity is conflicting (3, 4, 23, 25, 26)....
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...In the majority of clinical studies, pulmonary eosinophilia has been recognized as a predominant feature of the inflammatory infiltrate, which often correlates with disease severity (2-5, 14)....
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...In this model, aeroallergen challenge o f sensitized mice results in airways hyperreactivity to [3-methacholine (this airways spasmogen is used widely as a clinical tool to assess disease severity in asthmatic patients), severe pulmonary eosinophilic inflammation, and changes in lung morphology that closely parallel those observed in the asthmatic lung (1, 3)....
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TL;DR: Alveolar macrophages are part of the regulatory mechanisms of PMN mobility and adherence that appears to be crucial in the initiation of some inflammatory reactions, and this supports a central role for alveolarmacrophages in the regulation of PMn traffic in the lungs.
Abstract: Phagocytes, in particular macrophages and PMN, are now recognized as major components of inflammatory and immunologic reactions in the lung. Normally, macrophages represent the majority of phagocytes in the lower respiratory tract. These lung macrophages are morphologically and functionally heterogenous and include alveolar, interstitial, intravascular, and airway macrophages, each with characteristic morphologic and functional features. Through the presence of surface receptors for numerous ligands and through their large number of secretory products, lung macrophages can respond to environmental factors and account for most of the clearance of microparticles and microorganisms in the distal airways and the alveolar spaces. In addition, macrophages also play an important role in inflammatory processes through the release of oxygen radicals and proteolytic enzymes. Through the release of several cytokines, i.e., growth-promoting and inhibiting factors, lung macrophages may also influence both matrix damage and repair processes. Macrophages can also contribute to the alveolitis by recruitment of inflammatory and immune cells. This latter contribution is best demonstrated in migration movement of PMN. The normal distal airways generally contain a small number of PMN, but the pulmonary vascular bed represents a large reservoir of PMN. Some of them are in intimate contact with the endothelium, forming the so-called marginating pool of PMN. Because the capillary lumen is separated only from the alveolar space by a monolayer of endothelial and epithelial cells on each side of a thin interstitial matrix, it is likely that some inhibitory mechanism exists to prevent PMN from migrating towards the alveolar space. Such inhibitors of PMN migration are present both in serum and in the alveolar space, some being released by alveolar macrophages. However, alveolar macrophages can also secrete factors called chemotaxins that attract PMN to the airways, and this supports a central role for alveolar macrophages in the regulation of PMN traffic in the lungs. Thus, secretory products of alveolar macrophages are part of the regulatory mechanisms of PMN mobility and adherence that appears to be crucial in the initiation of some inflammatory reactions. The contribution of phagocytes to the defense against infection and tumor has been documented mostly in vitro. Thus, both oxygen radicals, in particular hydroxyl radicals and proteases such as lysozyme, are potent bactericidal agents. That phagocytes are also important defenders of the lungs in vivo is best supported by the observations in immunodeficient patients and animal models.(ABSTRACT TRUNCATED AT 400 WORDS)
1,094 citations
"Interleukin 5 deficiency abolishes ..." refers background in this paper
...Similarly, eosinophils and neutrophils, by releasing granular proteins, lipid mediators, and oxygen metabolites, also have the potential to induce pulmonary damage and airways hyperreactivity and to exacerbate the inflammatory response (10-13)....
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TL;DR: Bronchoalveolar lavage was performed in 19 asthmatic patients and in 5 control subjects to suggest that eosinophils and their mediators might be involved in the development of LAR after allergen inhalation.
Abstract: In order to obtain information about the nature of the local inflammatory process during late asthmatic reactions after house dust mite inhalation, bronchoalveolar lavage (BAL) was performed in 19 asthmatic patients and in 5 control subjects. In 16 of the patients and in all of the control subjects, BAL was performed 6 to 7 h after allergen inhalation. Six of the patients showed early and late asthmatic reactions (LAR), 5 showed early reactions, and 5 showed no reactions. Bronchoalveolar lavage was also performed shortly after the early reaction in 5 patients with documented combined early and late reactions. In the BAL fluid of the patients with LAR, a significant eosinophilia (0.01 less than p less than 0.05) was found compared with that in all other patient groups and with that in the control subjects. This bronchoalveolar eosinophilia was accompanied by elevated eosinophil cationic protein/albumin ratio in the BAL fluid (0.01 less than p less than 0.05). These observations suggest that eosinophils and their mediators might be involved in the development of LAR after allergen inhalation.
1,077 citations
"Interleukin 5 deficiency abolishes ..." refers background in this paper
...Clinical investigations show a correlation between the presence of activated inflammatory cells, histological changes to pulmonary tissue, and the development of airways hyperreactivity (2-5)....
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...In the majority of clinical studies, pulmonary eosinophilia has been recognized as a predominant feature of the inflammatory infiltrate, which often correlates with disease severity (2-5, 14)....
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TL;DR: Human rIL-5 was found to selectively stimulate morphological changes and the function of human eosinophils, and is thus a prime candidate for the selective eOSinophilia and eos inophil activation seen in disease.
Abstract: Human rIL-5 was found to selectively stimulate morphological changes and the function of human eosinophils. This molecule is thus a prime candidate for the selective eosinophilia and eosinophil activation seen in disease.
979 citations