A Study to Evaluate Safety and Efficacy of Mepolizumab in Patients with Moderate Persistent Asthma

Flood‐Page, Patrick; Swenson, Cheri A.; Faiferman, Isidore; Matthews, John G.; Williams, Michael J.A.; Brannick, Lesley; Robinson, Douglas S.; Wenzel, Sally E.; Busse, William W.; Hansel, Trevor T.; Barnes, Neil

doi:10.1164/rccm.200701-085oc

Cited by 693 publications

(447 citation statements)

References 39 publications

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“…IL-5 is a potent therapeutic target due to its causative relationship to eosinophilia. Therapies for asthma targeting IL-5 are currently being re-evaluated, and promising results have been obtained (47)(48)(49)(50). Therefore, innate IL-5-producing cells should be preferable candidates to study allergic diseases.…”

Section: Discussionmentioning

confidence: 99%

Identification of Innate IL-5–Producing Cells and Their Role in Lung Eosinophil Regulation and Antitumor Immunity

Ikutani

Yanagibashi

Ogasawara

et al. 2012

The Journal of Immunology

273

208

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IL-5 is involved in a number of immune responses such as helminth infection and allergy. IL-5 also plays roles in innate immunity by maintaining B-1 B cells and mucosal IgA production. However, the identity of IL-5–producing cells has not been unambiguously characterized. In this report, we describe the generation of an IL-5 reporter mouse and identify IL-5–producing non-T lymphoid cells that reside in the intestine, peritoneal cavity, and lungs in naive mice. They share many characteristics with natural helper cells, nuocytes, and Ih2 cells, including surface Ags and responsiveness to cytokines. However, these phenotypes do not completely overlap with any particular one of these cell types. Innate non-T IL-5–producing cells localized most abundantly in the lung and proliferated and upregulated IL-5 production in response to IL-25 and IL-33. IL-33 was more effective than IL-25. These cells contribute to maintaining sufficient numbers of lung eosinophils and are important for eosinophil recruitment mediated by IL-25 and IL-33. Given that eosinophils are shown to possess antitumor activity, we studied lung tumor metastasis and showed that innate IL-5–producing cells were increased in response to tumor invasion, and their regulation of eosinophils is critical to suppress tumor metastasis. Genetic blockade or neutralization of IL-5 impaired eosinophil recruitment into the lung and resulted in increased tumor metastasis. Conversely, exogenous IL-5 treatment resulted in suppressed tumor metastasis and augmented eosinophil infiltration. These newly identified innate IL-5–producing cells thus play a role in tumor surveillance through lung eosinophils and may contribute to development of novel immunotherapies for cancer.

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Section: Discussionmentioning

confidence: 99%

Identification of Innate IL-5–Producing Cells and Their Role in Lung Eosinophil Regulation and Antitumor Immunity

Ikutani

Yanagibashi

Ogasawara

et al. 2012

The Journal of Immunology

273

208

View full text Add to dashboard Cite

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“…These data suggested a key therapeutic target, but early clinical trials with anti-IL-5 monoclonal antibodies for atopic dermatitis, eosinophilic esophagitis, and asthma yielded mixed to negative results (Leckie et al, 2000;Oldhoff et al, 2005;Flood-Page et al, 2007). Although some of these findings may have reflected patient selection (Haldar et al, 2009;Bel et al, 2014;Ortega et al, 2014), these trials have not revealed a clear pathological role for eosinophils in allergic disease.…”

Section: Discussionmentioning

confidence: 99%

IgE-activated basophils regulate eosinophil tissue entry by modulating endothelial function

Cheng¹,

Sullivan²,

Retana³

et al. 2015

J Cell Biol

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Vertebrate immunity has evolved a modular architecture in response to perturbations. Allergic inflammation represents such a module, with signature features of antigen-specific IgE and tissue eosinophilia, although the cellular and molecular circuitry coupling these responses remains unclear. Here, we use genetic and imaging approaches in models of IgEdependent eosinophilic dermatitis to demonstrate a requisite role for basophils. After antigenic inflammation, basophils initiate transmigration like other granulocytes but, upon activation via their high-affinity IgE receptor, alter their migratory kinetics to persist at the endothelium. Prolonged basophil-endothelial interactions, in part dependent on activation of focal adhesion kinases, promote delivery of basophil-derived IL-4 to the endothelium and subsequent induction of endothelial vascular cell adhesion molecule-1 (VCAM-1), which is required for eosinophil accumulation. Thus, basophils are gatekeepers that link adaptive immunity with innate effector programs by altering access to tissue sites by activation-induced interactions with the endothelium.

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“…The inflammatory response in asthma is orchestrated by CD4 T h 2 cells inducing eosinophil infiltration and mast cell activation, followed by tissue remodeling, mucus hypersecretion, and airway hyperresponsiveness (3). While it is clear that immune mechanisms play a significant role in the development and maintenance of asthma, the limited efficacy of immune therapies suggests the involvement of additional mechanisms and physiological systems in the disease process (4).…”

mentioning

confidence: 99%

A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma

Caceres

Brackmann²,

Elia³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

400

386

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Asthma is an inflammatory disorder caused by airway exposures to allergens and chemical irritants. Studies focusing on immune, smooth muscle, and airway epithelial function revealed many aspects of the disease mechanism of asthma. However, the limited efficacies of immune-directed therapies suggest the involvement of additional mechanisms in asthmatic airway inflammation. TRPA1 is an irritant-sensing ion channel expressed in airway chemosensory nerves. TRPA1-activating stimuli such as cigarette smoke, chlorine, aldehydes, and scents are among the most prevalent triggers of asthma. Endogenous TRPA1 agonists, including reactive oxygen species and lipid peroxidation products, are potent drivers of allergen-induced airway inflammation in asthma. Here, we examined the role of TRPA1 in allergic asthma in the murine ovalbumin model. Strikingly, genetic ablation of TRPA1 inhibited allergen-induced leukocyte infiltration in the airways, reduced cytokine and mucus production, and almost completely abolished airway hyperreactivity to contractile stimuli. This phenotype is recapitulated by treatment of wild-type mice with HC-030031, a TRPA1 antagonist. HC-030031, when administered during airway allergen challenge, inhibited eosinophil infiltration and prevented the development of airway hyperreactivity. Trpa1 ؊/؊ mice displayed deficiencies in chemically and allergen-induced neuropeptide release in the airways, providing a potential explanation for the impaired inflammatory response. Our data suggest that TRPA1 is a key integrator of interactions between the immune and nervous systems in the airways, driving asthmatic airway inflammation following inhaled allergen challenge. TRPA1 may represent a promising pharmacological target for the treatment of asthma and other allergic inflammatory conditions. airway hyperreactivity ͉ TRP channel ͉ TRPA1

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A Study to Evaluate Safety and Efficacy of Mepolizumab in Patients with Moderate Persistent Asthma

Cited by 693 publications

References 39 publications

Identification of Innate IL-5–Producing Cells and Their Role in Lung Eosinophil Regulation and Antitumor Immunity

Identification of Innate IL-5–Producing Cells and Their Role in Lung Eosinophil Regulation and Antitumor Immunity

IgE-activated basophils regulate eosinophil tissue entry by modulating endothelial function

A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma

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