Dataset Information

Anti-IL-5 (mepolizumab) therapy reduces eosinophil activation ex vivo and increases IL-5 and IL-5 receptor levels.

ABSTRACT:

Background

Anti-IL-5 might be a useful therapeutic agent for eosinophilic disorders, yet its immunologic consequences have not been well characterized.

Objective

We sought to characterize the hematologic and immunologic effects of anti-IL-5 in human subjects.

Methods

The effects of 3-month infusions of mepolizumab were assessed in 25 patients with a variety of eosinophilic syndromes. Samples with increased IL-5 levels after therapy were analyzed by using size exclusion filtration. Immunoreactive IL-5 fraction and plasma samples were subsequently precipitated with saturating concentrations of protein A/G.

Results

Twenty-three patients responded to anti-IL-5 therapy with a decrease in blood eosinophil counts and a reduced percentage of CCR3(+) cells by 20- and 13-fold, respectively (P < .0001). Responsiveness was not related to the levels of baseline plasma IL-5 or the presence of FIP1L1-PDGFRA fusion gene. Persistently decreased blood eosinophilia remained for 3 months after final infusion in 76% of subjects. Therapy was associated with a large increase in blood IL-5 levels, likely because of a circulating IL-5/mepolizumab complex precipitated with protein A/G, a significant increase in eosinophil IL-5 receptor alpha expression, and increased percentage of CD4(+) and CD8(+) cells producing intracellular IL-5 (P < .05). Additionally, anti-IL-5 therapy decreased eotaxin-stimulated eosinophil shape change ex vivo.

Conclusions

Anti-IL-5 therapy induces a dramatic and sustained decrease in blood eosinophilia (including CCR3(+) cells), decreased eosinophil activation, and increased circulating levels of IL-5 in a variety of eosinophilic disorders. Increased levels of IL-5 receptor alpha and lymphocyte IL-5 production after anti-IL-5 therapy suggest an endogenous IL-5 autoregulatory pathway.

SUBMITTER: Stein ML

PROVIDER: S-EPMC2749495 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Publications

Anti-IL-5 (mepolizumab) therapy reduces eosinophil activation ex vivo and increases IL-5 and IL-5 receptor levels.

Stein Miguel L ML Villanueva Joyce M JM Buckmeier Bridget K BK Yamada Yoshiyuki Y Filipovich Alexandra H AH Assa'ad Amal H AH Rothenberg Marc E ME

The Journal of allergy and clinical immunology 20080414 6

<h4>Background</h4>Anti-IL-5 might be a useful therapeutic agent for eosinophilic disorders, yet its immunologic consequences have not been well characterized.<h4>Objective</h4>We sought to characterize the hematologic and immunologic effects of anti-IL-5 in human subjects.<h4>Methods</h4>The effects of 3-month infusions of mepolizumab were assessed in 25 patients with a variety of eosinophilic syndromes. Samples with increased IL-5 levels after therapy were analyzed by using size exclusion filt ...[more]

PMID: 18410960

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Project description:BackgroundMepolizumab and benralizumab are biologics approved for severe eosinophilic asthma. Mepolizumab is an anti-interlukin-5 (IL-5) antibody while benralizumab is an anti-interleukin-5 receptor alpha (IL-5R?) antibody targeting the IL-5 receptor on eosinophils. Both therapies reduce oral corticosteroid requirements and asthma exacerbations. However, no head-to-head studies have been published. The aim of the present study was to compare the efficacy of peripheral eosinophil reduction of mepolizumab and benralizumab.MethodsA retrospective chart review was conducted on patients with severe eosinophilic asthma who were approved for either IL-5 agent. Patients with noted non-adherence or those who were on fluctuating doses of corticosteroids for non-asthma related illnesses were excluded. The last detectable eosinophil count for each patient prior to start of therapy was compared to the highest eosinophil count noted after therapy start with at least 30 days of adherence.ResultsThirty-six patients taking mepolizumab and 19 patients taking benralizumab met the inclusion criteria and had both pre-treatment and post-treatment eosinophil counts. Baseline characteristics were not statistically different between those on mepolizumab and benralizumab therapy. The mean pre-therapy serum eosinophil count did not statistically differ between patients on mepolizumab (597.2 cells/µL) compared to benralizumab (521.6 cells/µL), p?=?0.3769. While both therapies resulted in a significant decrease in eosinophil count (p?<?0.0001); the mean decrease did not statistically differ between patients taking mepolizumab compared to those on benralizumab, p?=?0.9079. Nonetheless, 100% of patients receiving benralizumab had undetectable eosinophil counts post-therapy compared to 31% of patients receiving mepolizumab (p?<?0.0001).ConclusionBoth mepolizumab and benralizumab are potent targets of the IL-5 pathway with the ability to significantly reduce peripheral eosinophil counts. While there is there is no statistical difference in the magnitude of eosinophil reduction offered by each agent, benralizumab is able to decrease peripheral eosinophil counts to 0 cells/µL in more patients than mepolizumab.

Project description:BACKGROUND:Eosinophils are immunomodulatory leucocytes that contribute to the pathogenesis of Th2-driven asthma and allergic lung diseases. OBJECTIVE:Our goal was to identify unique properties of eosinophils recruited to the lungs and airways of mice in response to challenge with asthma-associated fungal allergens. METHODS:Mice were challenged intranasally on days 0, 3 and 6 with a filtrate of Alternaria alternata. Recruited eosinophils were enumerated in bronchoalveolar lavage fluid. Eosinophils were also isolated from lungs of mice sensitized and challenged with Aspergillus fumigatus and evaluated ex vivo in tissue culture. RESULTS:Eosinophils persist in the airways for several weeks in response to brief provocation with A. alternata in wild-type, Gm-csf- and eotaxin-1-gene-deleted mice, while eosinophils are recruited but do not persist in the absence of IL-13. Eosinophils isolated from the lungs A. alternata-challenged mice are cytokine-enriched compared to those from IL5tg mice, including 800-fold higher levels of eotaxin-1. Furthermore, eosinophils from the lungs and spleen of fungal allergen-challenged wild-type mice are capable of prolonged survival ex vivo, in contrast to eosinophils from both untreated and fungal allergen-challenged IL5tg mice, which undergo rapid demise in the absence of exogenous cytokine support. TNF-? (but not IL5, IL-3, eotaxin-1 or GM-CSF) was detected in supernatants of ex vivo eosinophil cultures from the lungs of fungal allergen-challenged wild-type mice. However, neither TNF-? gene deletion nor anti-TNF-? neutralizing antibodies had any impact sustained eosinophil survival ex vivo. CONCLUSION AND CLINICAL RELEVANCE:Eosinophils are phenotypically and functionally heterogeneous. As shown here, eosinophils from fungal allergen-challenged wild-type mice maintain a distinct cytokine profile, and, unlike eosinophils isolated from IL5tg mice, they survive ex vivo in the absence of exogenous pro-survival cytokine support. As treatments for asthma currently in development focus on limiting eosinophil viability via strategic cytokine blockade, the molecular mechanisms underlying differential survival merit further investigation.

Project description:RationaleMepolizumab, an IL-5-blocking antibody, reduces exacerbations in patients with severe eosinophilic asthma. Mepolizumab arrests eosinophil maturation; however, the functional phenotype of eosinophils that persist in the blood and airway after administration of IL-5 neutralizing antibodies has not been reported.ObjectivesTo determine the effect of anti-IL-5 antibody on the numbers and phenotypes of allergen-induced circulating and airway eosinophils.MethodsAirway inflammation was elicited in participants with mild allergic asthma by segmental allergen challenge before and 1 month after a single intravenous 750-mg dose of mepolizumab. Eosinophils were examined in blood, bronchoalveolar lavage, and endobronchial biopsies 48 hours after challenge.Measurements and main resultsSegmental challenge without mepolizumab induced a rise in circulating eosinophils, bronchoalveolar lavage eosinophilia, and eosinophil peroxidase deposition in bronchial mucosa. IL-5 neutralization before allergen challenge abolished the allergen-induced rise in circulating eosinophils and expression of IL-3 receptors, whereas airway eosinophilia and eosinophil peroxidase deposition were blunted but not eliminated. Before mepolizumab treatment, bronchoalveolar lavage eosinophils had more surface IL-3 and granulocyte-monocyte colony-stimulating factor receptors, CD69, CD44, and CD23 and decreased IL-5 and eotaxin receptors than blood eosinophils. This activation phenotype indicated by bronchoalveolar lavage eosinophil surface markers, as well as the release of eosinophil peroxidase by eosinophils in the bronchial mucosa, was maintained after mepolizumab.ConclusionsMepolizumab reduced airway eosinophil numbers but had a limited effect on airway eosinophil activation markers, suggesting that these cells retain functionality. This observation may explain why IL-5 neutralization reduces but does not completely eradicate asthma exacerbations. Clinical trial registered with www.clinicaltrials.gov (NCT00802438).

Dataset Information

Anti-IL-5 (mepolizumab) therapy reduces eosinophil activation ex vivo and increases IL-5 and IL-5 receptor levels.

Background

Objective

Methods

Results

Conclusions

Publications

Anti-IL-5 (mepolizumab) therapy reduces eosinophil activation ex vivo and increases IL-5 and IL-5 receptor levels.

Similar Datasets

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