Anti–IL-5 (mepolizumab) therapy induces bone marrow eosinophil maturational arrest and decreases eosinophil progenitors in the bronchial mucosa of atopic asthmatics

Menzies‐Gow, Andrew; Flood‐Page, Patrick; Sehmi, Roma; Burman, J. F.; Hamid, Qutayba; Robinson, Douglas S.; Kay, A. B.; Denburg, Judah A.

doi:10.1067/mai.2003.1382

Cited by 245 publications

(194 citation statements)

References 24 publications

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“…[1][2][3] Despite available care, recurrent asthma exacerbations are a major issue in a subgroup of patients with eosinophilic airway inflammation. [4][5][6] Mepolizumab, a humanized monoclonal antibody against interleukin-5, selectively inhibits eosinophilic inflammation 7,8 and reduces the number of eosinophils in both sputum and blood, resulting in a reduction in exacerbations and in the need for treatment with systemic glucocorticoids. [7][8][9][10][11][12] In the Dose Ranging Efficacy and Safety with Mepolizumab (DREAM) study 13 of intravenous mepolizumab, investigators defined key phenotypic characteristics of the target population that were associated with a response to treatment with mepolizumab.…”

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confidence: 99%

“…[4][5][6] Mepolizumab, a humanized monoclonal antibody against interleukin-5, selectively inhibits eosinophilic inflammation 7,8 and reduces the number of eosinophils in both sputum and blood, resulting in a reduction in exacerbations and in the need for treatment with systemic glucocorticoids. [7][8][9][10][11][12] In the Dose Ranging Efficacy and Safety with Mepolizumab (DREAM) study 13 of intravenous mepolizumab, investigators defined key phenotypic characteristics of the target population that were associated with a response to treatment with mepolizumab. In our study, called Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma (MENSA), we used these key characteristics (i.e., blood eosinophil count, number of previous exacerbations, and dose of inhaled glucocorticoids) to identify eligible patients in a placebo-controlled comparison of subcutaneous and intravenous administration of mepolizumab.…”

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confidence: 99%

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Mepolizumab Treatment in Patients with Severe Eosinophilic Asthma

Liu²,

et al. 2014

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confidence: 99%

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Mepolizumab Treatment in Patients with Severe Eosinophilic Asthma

Liu²,

et al. 2014

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“…Eosinophils actively contribute to airway wall remodelling in allergic asthma in humans [26]. Suppression of blood eosinophilia by S. pneumoniae infection may be significant for the long-term inhibition of eosinophil accumulation in the lungs, leading to the inhibition or resolution of pathogenesis and remodelling events [27]. Thus, the features of AAD that were not reduced in the short term by infection may be resolved in the longer term.…”

Section: Discussionmentioning

confidence: 99%

Streptococcus pneumoniae infection suppresses allergic airways disease by inducing regulatory T-cells

Preston¹,

Thorburn²,

Starkey³

et al. 2010

European Respiratory Journal

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An inverse association exists between some bacterial infections and the prevalence of asthma. We investigated whether Streptococcus pneumoniae infection protects against asthma using mouse models of ovalbumin (OVA)-induced allergic airway disease (AAD).Mice were intratracheally infected or treated with killed S. pneumoniae before, during or after OVA sensitisation and subsequent challenge. The effects of S. pneumoniae on AAD were assessed.Infection or treatment with killed S. pneumoniae suppressed hallmark features of AAD, including antigen-specific T-helper cell (Th) type 2 cytokine and antibody responses, peripheral and pulmonary eosinophil accumulation, goblet cell hyperplasia, and airway hyperresponsiveness. The effect of infection on the development of specific features of AAD depended on the timing of infection relative to allergic sensitisation and challenge. Infection induced significant increases in regulatory T-cell (Treg) numbers in lymph nodes, which correlated with the degree of suppression of AAD. Tregs reduced T-cell proliferation and Th2 cytokine release. The suppressive effects of infection were reversed by anti-CD25 treatment.Respiratory infection or treatment with S. pneumoniae attenuates allergic immune responses and suppresses AAD. These effects may be mediated by S. pneumoniae-induced Tregs. This identifies the potential for the development of therapeutic agents for asthma from S. pneumoniae.

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“…Mepolizumab is a fully humanized anti-IL-5 monoclonal antibody that produces rapid, marked, and sustained reductions in eosinophil counts (Table III) [40][41][42]. The effect of mepolizumab appears to be due to the Arresting of eosinophil maturation within the bone marrow [42].…”

Section: Future Strategies For Managing Hes: Targeting Il-5mentioning

confidence: 99%

Hypereosinophilic syndrome: An update

et al. 2005

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Hypereosinophilic syndrome (HES) is a rare disorder that is characterized by persistent and marked eosinophilia combined with organ system dysfunction. HES has substantial clinical heterogeneity but can be fatal without treatment, especially in patients who present with a myelodysplastic variant of the disorder. Although the pathophysiology of HES is poorly defined, dysregulation of cytokines (interleukin 5 [IL-5], IL-3, granulocyte-macrophage colony-stimulating factor [GM-CSF]) responsible for the maturation of eosinophils is a primary feature. Of these cytokines, IL-5 appears to have the greatest role in the regulation of eosinophil maturation. There is no Food and Drug Administration-approved treatment for HES as yet; current strategies are designed to lower blood eosinophils and attempt to limit end-organ damage. Historically, corticosteroids and cytotoxic agents have been the mainstays of therapy, with biological response modifiers such as interferon-alpha also effective in some patients. However, despite improvements in survival, available agents have significant limitations in terms of efficacy, tolerability, and long-term toxicity. More recently, new agents directed at specific targets in the pathogenesis of HES have been developed. These include imatinib mesylate, a tyrosine kinase inhibitor, and more recently, mepolizumab, an anti-IL-5 monoclonal antibody. In a small case series of patients, these agents have been shown to produce hematological and clinical responses in patients with HES, although they may be effective in different subsets of patients. These targeted therapies have the potential to improve clinical outcomes and to further the understanding the pathophysiology of this difficult-to-treat condition. Am.

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Anti–IL-5 (mepolizumab) therapy induces bone marrow eosinophil maturational arrest and decreases eosinophil progenitors in the bronchial mucosa of atopic asthmatics

Cited by 245 publications

References 24 publications

Mepolizumab Treatment in Patients with Severe Eosinophilic Asthma

Mepolizumab Treatment in Patients with Severe Eosinophilic Asthma

Streptococcus pneumoniae infection suppresses allergic airways disease by inducing regulatory T-cells

Hypereosinophilic syndrome: An update

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