Inhibition of the IL-4/IL-13 receptor system prevents allergic sensitization without affecting established allergy in a mouse model for allergic asthma

Hahn, Christian; Teufel, Martin; Herz, Udo; Renz, Harald; Erb, Klaus J.; Wohlleben, Gisela; Bröcker, Eva B.; Duschl, Albert; Sebald, Walter; Grünewald, Susanne

doi:10.1067/mai.2003.1527

Cited by 62 publications

(45 citation statements)

References 35 publications

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“…However, IL-4 BAL levels were strongly decreased after combined C3aR and C5aR inhibition. IL-4 is a typical Th2 cytokine, the major function of which is to differentiate B cells and to induce B cell isotope switch to IgE during sensitization (49). During the effector phase of the allergic response, mast cells, basophils, and T cells are considered the main source of IL-4 (21,22,50).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Targeting of Anaphylatoxin Receptors during the Effector Phase of Allergic Asthma Suppresses Airway Hyperresponsiveness and Airway Inflammation

Baelder

Fuchs

Bautsch³

et al. 2005

The Journal of Immunology

101

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Airway hyperresponsiveness and airway inflammation are hallmarks of allergic asthma, the etiology of which is crucially linked to the presence of Th2 cytokines. A role for the complement anaphylatoxins C3a and C5a in allergic asthma was suggested, as deficiencies of the C3a receptor (C3aR) and of complement factor C5 modulate airway hyperresponsiveness, airway inflammation, and Th2 cytokine levels. However, such models do not allow differentiation of effects on the sensitization phase and the effector phase of the allergic response, respectively. In this study, we determined the role of the anaphylatoxins on the effector phase of asthma by pharmacological targeting of the anaphylatoxin receptors. C3aR and C5a receptor (C5aR) signaling was blocked using the nonpeptidic C3aR antagonist SB290157 and the neutralizing C5aR mAb 20/70 in a murine model of Aspergillus fumigatus extract induced pulmonary allergy. Airway hyperresponsiveness was substantially improved after C5aR blockade but not after C3aR blockade. Airway inflammation was significantly reduced in mice treated with the C3aR antagonist or the anti-C5aR mAb, as demonstrated by reduced numbers of neutrophils and eosinophils in bronchoalveolar lavage fluid. Of note, C5aR but not C3aR inhibition reduced lymphocyte numbers in bronchoalveolar lavage fluid. Cytokine levels of IL-5 and IL-13 in bronchoalveolar lavage fluid were not altered by C3aR or C5aR blockade. However, blockade of both anaphylatoxin receptors markedly reduced IL-4 levels. These data suggest an important and exclusive role for C5aR signaling on the development of airway hyperresponsiveness during pulmonary allergen challenge, whereas both anaphylatoxins contribute to airway inflammation and IL-4 production.

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Section: Discussionmentioning

confidence: 99%

Pharmacological Targeting of Anaphylatoxin Receptors during the Effector Phase of Allergic Asthma Suppresses Airway Hyperresponsiveness and Airway Inflammation

Baelder

Fuchs

Bautsch³

et al. 2005

The Journal of Immunology

101

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“…There is evidence that the IgE memory response is not influenced by IL-4, IL-13 and their antagonists and hence may be difficult to control by any cytokine-based treatment [46]. …”

Section: Discussionmentioning

confidence: 99%

Antigens Drive Memory IgE Responses in Human Allergy via the Nasal Mucosa

Niederberger¹,

Ring

Rakoski

et al. 2006

Int Arch Allergy Immunol

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Background: Natural allergen contact induces an increase of IgE levels and sensitivity but the mechanisms underlying the allergen-specific memory responses are poorly understood. Furthermore, it has not been studied whether allergen exposure affects the molecular reactivity profiles in patients. The aim of this study was to analyze the influence of nasal allergen encounter on the molecular profile and magnitude of memory IgE responses and on systemic sensitivity. Methods: We investigated allergen-specific IgE, IgG subclass and IgM responses to defined allergen molecules (grass pollen: Phl p 1, Phl p 2 and Phl p 5; birch pollen: Bet v 1 and Bet v 2) in allergic patients in response to natural as well as to controlled nasal and dermal allergen exposure. Changes in systemic sensitivity were monitored by skin prick testing and by basophil histamine release experiments. Results: Respiratory antigen exposure boosted IgE levels to a pre-established profile of allergen molecules without inducing significant IgM responses or new IgE specificities in allergic individuals. The importance of the route of allergen contact is demonstrated by an increase of systemic IgE levels and sensitivity after nasal exposure. In vitro sensitisation of basophils with pre- and post-seasonal serum samples suggests an allergen-induced elevation of specific IgE as a cause for the increased allergen-specific sensitivity. Conclusion: The characteristics of the allergen-driven antibody responses indicate a direct activation of an established pool of IgE memory cells with defined specificities as an underlying mechanism. Our finding that nasal allergen contact is a major factor for the boosting of memory IgE and systemic sensitivity may open new therapeutic possibilities.

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“…Development of allergic airway disease can also be induced by systemic administration of allergen alone without adjuvant followed by airway challenge [35, 36, 37]or, in the absence of systemic sensitization, by repeated administration of allergen directly into the lung either by inhalation [38, 39], intranasal [40, 41]or intratracheal [42]instillation. Administration of antigen-pulsed dendritic cells into the airways can also prime animals to develop airway disease following limited inhaled allergen exposure [43, 44].…”

Section: Lessons Learned From Murine Modelsmentioning

confidence: 99%

Insights into the Pathogenesis of Asthma Utilizing Murine Models

Taube¹,

Dakhama²,

Gelfand³

2004

Int Arch Allergy Immunol

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Asthma is a common syndrome in children and adults. Despite the increasing prevalence and socioeconomic burden, the underlying pathophysiology remains poorly defined in a large percentage of asthmatics. Animal models and, in particular, murine models of allergic airway disease have helped to reveal some of the potential underlying mechanisms and have played an important role in identifying the importance of T cells and T_H2 cytokines in development of allergen-induced inflammation and airway hyperresponsiveness. In addition, other cell types including mast cells and eosinophils have been implicated in the development of some aspects of the disease. To further understand this complex syndrome, the development of animal models which mimic elements of this chronic airway disease is essential.

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Inhibition of the IL-4/IL-13 receptor system prevents allergic sensitization without affecting established allergy in a mouse model for allergic asthma

Cited by 62 publications

References 35 publications

Pharmacological Targeting of Anaphylatoxin Receptors during the Effector Phase of Allergic Asthma Suppresses Airway Hyperresponsiveness and Airway Inflammation

Pharmacological Targeting of Anaphylatoxin Receptors during the Effector Phase of Allergic Asthma Suppresses Airway Hyperresponsiveness and Airway Inflammation

Antigens Drive Memory IgE Responses in Human Allergy via the Nasal Mucosa

Insights into the Pathogenesis of Asthma Utilizing Murine Models

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