Interleukin-4 Receptor in Moderate Atopic Asthma

Borish, Larry; Nelson, Harold S.; Lanz, Miguel J.; Claussen, Lori; Whitmore, James B.; Agosti, Jan M.; Garrison, Leslie

doi:10.1164/ajrccm.160.6.9808146

Cited by 385 publications

(51 citation statements)

References 34 publications

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“…Clinical studies are currently ongoing to examine the effects of sIL-4R treatment on airway inflammation and function in patients with persistent asthma. In a phase I/II study in 25 patients with moderate persistent asthma who required inhaled corticosteroids for control of symptoms, after removal of corticosteroids, a single 1500 g nebulization of sIL-4R stabilized lung function and decreased exhaled NO, a marker of pulmonary inflammation during the first week after sIL-4R inhalation (56). Moderation of lung cellular inflammation and mucus hypersecretion by sIL-4R in a mouse model of asthma suggests that sIL-4R may be useful in the treatment of patients with asthma.…”

Section: Discussionmentioning

confidence: 99%

Soluble IL-4 Receptor Inhibits Airway Inflammation Following Allergen Challenge in a Mouse Model of Asthma

Henderson¹,

Emil

Maliszewski³

2000

The Journal of Immunology

149

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In vitro and in vivo studies, in both animal models and human asthmatics, have implicated IL-4 as an important inflammatory mediator in asthma. In a murine asthma model, we examined the anti-inflammatory activities of soluble IL-4R (sIL-4R). In this model, mice sensitized to OVA by i.p. and intranasal (i.n.) routes are challenged with the allergen by i.n. administration. The OVA challenge elicits an eosinophil infiltration into the lungs, with widespread mucus occlusion of the airways, and results in bronchial hyperreactivity. sIL-4R (0.1–100 μg) was administered by either i.n. or i.p. routes before OVA challenge in OVA-sensitized mice. Both blood and bronchoalveolar lavage fluid levels of sIL-4R were significantly elevated compared with controls by i.n. delivery of 100 μg sIL-4R; i.p. delivery of 100 μg sIL-4R only raised blood levels of sIL-4R. The i.n. administration of 100 μg sIL-4R before allergen challenge significantly reduced late phase pulmonary inflammation, blocking airway eosinophil infiltration, VCAM-1 expression, and mucus hypersecretion. In contrast, i.p. delivery of 100 μg sIL-4R inhibited only the influx of eosinophils into the lungs, but not airway mucus release. Furthermore, sIL-4R treatment by either i.n. or i.p. routes did not reduce airway hyperreactivity in response to methacholine challenge. Thus, elevating airway levels of sIL-4R through the administration of exogenous sIL-4R is effective in blocking the late phase pulmonary inflammation that occurs in this murine allergen-challenge asthma model. These results suggest that sIL-4R may have beneficial anti-inflammatory effects in asthmatic patients.

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Section: Discussionmentioning

confidence: 99%

Soluble IL-4 Receptor Inhibits Airway Inflammation Following Allergen Challenge in a Mouse Model of Asthma

Henderson¹,

Emil

Maliszewski³

2000

The Journal of Immunology

149

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“…On the other hand, some studies have indicated the importance of IL-4 in promoting allergic inflammation at an effector phase by inducing the recruitment of Th2 cells in part via vascular cell adhesion molecule-1/very late antigen-4-dependent mechanisms [8, 9]. In addition, a clinical trial of soluble IL-4 receptor (IL-4R) that neutralizes IL-4 function showed the therapeutic benefit in moderately severe asthma [10]. Therefore, IL-4 could play a role in the induction of allergic inflammation in a sensitized individual, but the relative importance of IL-4 depends on the state of sensitization and/or genetic background.…”

Section: Role Of Classical Th2 Cytokines In Causing Allergic Inflammamentioning

confidence: 99%

Role of Cytokines in Allergic Airway Inflammation

Nakajima

Takatsu

2006

Int Arch Allergy Immunol

137

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Asthma is characterized by intense infiltration of eosinophils and CD4+ T cells into the submucosal tissue of airways. Accumulating evidence indicates that T helper type 2 cell-derived cytokines such as interleukin (IL)-4, IL-5 and IL-13 play critical roles in orchestrating and amplifying allergic inflammation in asthma. In addition, it has been suggested that newly identified cytokines including thymic stromal lymphopoietin, IL-25 and IL-33 are involved in the induction of allergic inflammation in asthma. In this review, we discuss the role of individual cytokines in the pathogenesis of asthma.

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“…However, in a collaborative study we have shown that administration of a blocking monoclonal antibody against IL-5 to atopic asthmatics had no effect on the allergen-provoked early and late bronchoconstrictor responses or BHR, even though it reduced the baseline and postallergen increase in circulating and sputum eosinophils by 90 and 70%, respectively [4], and, in a recent 12-week clinical trial, anti-IL-5 failed to reveal efficacy [5]. In contrast, antagonising IL-4 with a soluble decoy receptor (sIL-4R) stabilised lung function in the face of corticosteroid reduction [6]. IL-4 and its structural homologue, IL-13, are key cytokines in asthma both on account of their pro-inflammatory role and their effects on epithelial cells and fibroblasts linked to airway wall remodelling in transgenic animal models [7].…”

Section: Introductionmentioning

confidence: 99%

Invited Lecture: Activation of the Epithelial Mesenchymal Trophic Unit in the Pathogenesis of Asthma

Holgate

Lackie

Howarth

et al. 2001

Int Arch Allergy Immunol

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Background: A recent NIH Workshop and an ERS Task Force concluded that more work was needed to understand mechanisms of severe and chronic asthma. This report describes a series of studies that identify aberrant epithelial mesenchymal signalling in the airways as an important event in maintaining inflammation and driving remodelling in response to environmental injury. Methods: Immunohistochemistry, genotyping and functional studies conducted on cultured asthmatic cells and mucosal biopsies were used to identify biochemical pathways involved in epithelial injury and repair in asthma and their relationship to disease severity. Results: Our findings suggest that the asthmatic state results from an interaction between a susceptible epithelium and Th-2-mediated inflammation to alter the communication between the epithelium and the underlying mesenchyme – the epithelial mesenchymal trophic unit – leading to disease persistence, airway remodelling and refractoriness to corticosteroid treatment. Conclusions: Asthma is more than an inflammatory disorder, but requires engagement of important signalling pathways involved in epithelial repair and tissue remodelling. These pathways involving EGFRs and TGF-βRs provide targets against which to develop novel therapies for chronic asthma.

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Interleukin-4 Receptor in Moderate Atopic Asthma

Abstract: A single dose of IL-4R appears safe and effective in moderate asthma. The 1,500 microg dose appears as safe but significantly more effective than the 500 microg dose.

Cited by 385 publications

References 34 publications

Soluble IL-4 Receptor Inhibits Airway Inflammation Following Allergen Challenge in a Mouse Model of Asthma

Soluble IL-4 Receptor Inhibits Airway Inflammation Following Allergen Challenge in a Mouse Model of Asthma

Role of Cytokines in Allergic Airway Inflammation

Invited Lecture: Activation of the Epithelial Mesenchymal Trophic Unit in the Pathogenesis of Asthma

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