Involvement of distal airways in a chronic model of experimental asthma

Wegmann, Michael; Fehrenbach, Heinz; Fehrenbach, Antonia; Held, T.; Schramm, Christoph; Garn, Holger; Renz, Harald

doi:10.1111/j.1365-2222.2005.02306.x

Cited by 82 publications

(99 citation statements)

References 36 publications

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“…Airway epithelial mucus was identified by means of PAS staining. The surface area of mucuscontaining goblet cells (S gc ) per total surface area of airway epithelial basal membrane (S ep ) and the volume of PAS-stained epithelial mucus (V mucus ) per S ep were determined using a computer-assisted stereology tool (newCAST s ; Hiersholm, Visiopharm, Denmark) according to the formulas [33].…”

Section: Lung Histology and Quantificationmentioning

confidence: 99%

Selective depletion of Foxp3⁺ Treg during sensitization phase aggravates experimental allergic airway inflammation

et al. 2010

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Recent studies highlight the role of Treg in preventing unnecessary responses to allergens and maintaining functional immune tolerance in the lung. We investigated the role of Treg during the sensitization phase in a murine model of experimental allergic airway inflammation by selectively depleting the Treg population in vivo. DEpletion of REGulatory T cells (DEREG) mice were depleted of Treg by diphtheria toxin injection. Allergic airway inflammation was induced using OVA as a model allergen. Pathology was assessed by scoring for differential cellular infiltration in bronchoalveolar lavage, IgE and IgG1 levels in serum, cytokine secretion analysis of lymphocytes from lung draining lymph nodes and lung histology. Use of DEREG mice allowed us for the first time to track and specifically deplete both CD25 1 and CD25 À Foxp31 Treg, and to analyze their significance in limiting pathology in allergic airway inflammation. We observed that depletion of Treg during the priming phase of an active immune response led to a dramatic exacerbation of allergic airway inflammation in mice, suggesting an essential role played by Treg in regulating immune responses against allergens as early as the sensitization phase via maintenance of functional tolerance. Key words: Allergic airway inflammation . Depletion of regulatory T cells (DEREG). IntroductionThere has been a dramatic increase in prevalence of allergic disorders such as allergic rhinitis (hay fever), atopic dermatitis (eczema) and asthma in the past few decades, especially in developed countries [1,2]. Given that allergic airway inflammation has been associated with dysregulated Th2 immune response [3], the increased prevalence of allergy has been explained by the revised hygiene hypothesis [4,5]. This hypothesis suggests that early childhood infections prime immune-regulation and mediate protection from allergies by driving development of regulatory mechanisms rather than provoking aggressive immune responses [6,7]. This definition, in an extension of the original hygiene hypothesis proposing a Th1- . However, a similar approach also employing CD25 1 T-cell depletion produced conflicting results, demonstrating reduced Th2 cytokine production and no effect on eosinophilic inflammation [16]. Conversely, another study shows that mice pretransplanted with CD4 + CD25 + T-celldepleted splenocytes exhibited decreased antigen-induced eosinophil recruitment into the airways and reduced Th2 differentiation and cytokine production which were restored on supplementation with CD25 1 T cell fraction [17]. Finally, mouse strain-specific differences have been observed in the course of CD25 1 T-cell depletion, where depletion of Treg in an allergy resistant strain of mice C3H led to massive exacerbation of airway inflammation, while Treg depletion in the allergic sensitive mice strain A/J showed only mild differences [14]. Although most of the work has been focused on CD25 ResultsTreg depletion leads to enhanced eosinophil infiltration in BAL fluid in an inflammation modelTo examine ...

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Section: Lung Histology and Quantificationmentioning

confidence: 99%

Selective depletion of Foxp3⁺ Treg during sensitization phase aggravates experimental allergic airway inflammation

et al. 2010

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“…Prolonging allergen exposure in sensitized animals has been reported to be associated with a disappearance of the inflammatory changes (7)(8)(9)(10). Several research groups have been searching for ways to avoid this waning of inflammation to mimic more closely the chronic nature of human asthma (10)(11)(12)(13). However, we appreciated this fading away of inflammation as important, since it essentially models the control of unwanted airway inflammation.…”

Section: Clinical Relevancementioning

confidence: 99%

Prolonged Inhaled Allergen Exposure Can Induce Persistent Tolerance

Hove

Maes

Joos

et al. 2007

Am J Respir Cell Mol Biol

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Murine asthma models suggest that failure of immune tolerance rather than a defective T helper cell type 1 (Th1) immunity underlies the immune biology of Th2-driven allergen-induced airway disease. Intriguingly, prolonged exposures can result in a full waning of inflammation. The mechanisms underlying this observation are not understood. We hypothesized that the fading of inflammation is the result of regulatory processes, characterized by altered dendritic cell (DC)-T cell interactions. First, we implemented a model in which mice developed Th2-driven airway disease. When we subjected these mice to prolonged antigen ovalbumin (OVA) exposures (8 wk), all inflammation disappeared. Re-immunization and re-challenge showed an inability to mount Th2-skewed immune responses, with absence of airway eosinophils, IgE, and Th2 cytokines. Besides specific immune tolerance, bystander protection was observed. A decrease in CD4 ϩ CD25 ϩ Foxp3 ϩ T-regulatory cells, PD-1, and IL-10 expression was discerned as compared with acute inflammation. In addition, suppression of ICOS and CD28 was found, along with inhibited DC maturation. This process of disease inhibition surprisingly had a long-lasting memory and was not caused by endotoxin signaling through TLR-4. In summary, our results indicate that the disappearance of Th2-driven airway disease upon persistent antigen exposure is associated with the induction of immune tolerance. The tolerant state is antigen-dependent, and extends to bystander antigens. Moreover, this tolerance is characterized by an altered DC-T cell communication and is long-lasting. Our data further suggest that the mechanism of the disease inhibition after allergic airway inflammation differs from the anti-inflammatory mechanisms observed during acute eosinophilic airway inflammation.

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“…However, TGF-b1 is associated with airway smooth muscle remodelling in the OVA mouse model of allergic airways disease [62,95]. Smooth muscle hypertrophy and hyperplasia is a characteristic of the distribution of airway smooth muscle in remodelling airways in humans [96].…”

Section: Mesenchymal Cellsmentioning

confidence: 99%

“…However, the role of FGF-2 released from the BMZ and its interactions with basal cells of the airway epithelium has not been determined. In chronic exposure to OVA, mice show markedly increased levels of transforming growth factor (TGF)-b and subepithelial fibrosis throughout the airway tree [62].…”

Section: Epithelial Changes In Asthmamentioning

confidence: 99%

“…In humans, increases in airway smooth muscle are likely to be the primary mechanism causing AHR, and changes in the extracellular matrix may stimulate smooth muscle growth and contribute to the mechanics of airway obstruction. The classic chicken-egg ovalbumin (OVA) intraperitoneal immunisation with alum, followed by repetitive challenge with OVA intranasally, produces a robust eosinophilic inflammatory response around bronchi and allergen-dependent AHR, dependent on CD4+ T-lymphocytes via IL-4, but independent of IL-5, immunoglobulin (Ig)E, or both [61,62]. However, there are other unique features of allergic airways disease that are found in humans but not mice: a lack of intrinsic AHR (except in the A/J mouse strain), smooth muscle hypertrophy in the more distal bronchi and respiratory bronchioles, exfoliation of epithelial sheets, and mast cell infiltration of airway smooth muscle [60].…”

Section: Airway-specific Responses To Inhaled Allergensmentioning

confidence: 99%

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Asthma: a comparison of animal models using stereological methods

Hyde

Miller

Schelegle

et al. 2006

European Respiratory Review

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Asthma is a worldwide health problem that affects 300 million people, as estimated by the World Health Organization. A key question in light of this statistic is: ''what is the most appropriate laboratory animal model for human asthma?''The present authors used stereological methods to assess airways in adults and during postnatal development, and their response to inhaled allergens to compare rodents and nonhuman primates to responses in humans.An epithelial-mesenchymal trophic unit was defined in which all of the compartments interact with each other. Asthma manifests itself by altering not only the epithelial compartment but also other compartments (e.g. interstitial, vascular, immunological and nervous). All of these compartments show significant alteration in an airway generation-specific manner in rhesus monkeys but are limited to the proximal airways in mice. The rhesus monkey model shares many of the key features of human allergic asthma including the following: 1) allergen-specific immunoglobulin (Ig)E and skin-test positivity; 2) eosinophils and IgE+ cells in airways; 3) a Thelper type 2 cytokine profile in airways; 4) mucus cell hyperplasia; 5) subepithelial fibrosis; 6) basement membrane thickening; and 7) persistent baseline hyperreactivity to histamine or methacholine.In conclusion, the unique responses to inhaled allergens shown in rhesus monkeys make it the most appropriate animal model of human asthma.

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Involvement of distal airways in a chronic model of experimental asthma

Abstract: These data indicate that our model of chronic aerosol allergen challenges leads to a phenotype of experimental asthma with participation of distal airways and persistence of inflammation thereby resembling many morphological and physiological aspects of human bronchial asthma.

Cited by 82 publications

References 36 publications

Selective depletion of Foxp3⁺ Treg during sensitization phase aggravates experimental allergic airway inflammation

Selective depletion of Foxp3⁺ Treg during sensitization phase aggravates experimental allergic airway inflammation

Prolonged Inhaled Allergen Exposure Can Induce Persistent Tolerance

Asthma: a comparison of animal models using stereological methods

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Involvement of distal airways in a chronic model of experimental asthma

Abstract: These data indicate that our model of chronic aerosol allergen challenges leads to a phenotype of experimental asthma with participation of distal airways and persistence of inflammation thereby resembling many morphological and physiological aspects of human bronchial asthma.

Cited by 82 publications

References 36 publications

Selective depletion of Foxp3+ Treg during sensitization phase aggravates experimental allergic airway inflammation

Selective depletion of Foxp3+ Treg during sensitization phase aggravates experimental allergic airway inflammation

Prolonged Inhaled Allergen Exposure Can Induce Persistent Tolerance

Asthma: a comparison of animal models using stereological methods

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Product

Resources

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Selective depletion of Foxp3⁺ Treg during sensitization phase aggravates experimental allergic airway inflammation

Selective depletion of Foxp3⁺ Treg during sensitization phase aggravates experimental allergic airway inflammation