Molecular and clinical rationale for therapeutic targeting of interleukin‐5 and its receptor

Molfino, Néstor A.; Gossage, David L.; Kolbeck, Roland; Parker, J.D.; Geba, Gregory P.

doi:10.1111/j.1365-2222.2011.03854.x

Cited by 190 publications

(149 citation statements)

References 243 publications

(288 reference statements)

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“…IL-5 is a marker for the Th2 phenotype and has an important role in allergy. IL-5 is involved in the differentiation and maturation of eosinophils and in the migration of eosinophils to tissue sites in the presence of an allergic response and has been identified across animal models as being a key common denominator in allergic inflammatory pathways [23][24][25].…”

Section: Resultsmentioning

confidence: 99%

Adjuvant effect of zymosan after pulmonary treatment in a mouse ovalbumin allergy model

Young

Wolfarth

Roberts

et al. 2013

Experimental Lung Research

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An association has been observed between indoor mold contamination and lung allergy and asthma. This relationship is not fully understood. 1→3-β-Glucan is the major cell wall component of fungi and a good marker of fungi exposure. The objective was to evaluate the adjuvant effect of zymosan, a crude yeast cell wall preparation of 1→3-β-glucan, during ovalbumin (OVA) sensitization in an allergy model. BALB/c mice were sensitized by pharyngeal aspiration with saline, 50 µg of OVA, or OVA with 1, 10, 50, or 75 µg of zymosan on days 0, 7, and 14. One week after sensitization, each sensitized animal group was challenged with an aspiration dose of 50 µg of OVA once a week for 2 weeks. At 1 day after the last aspiration, bronchoalveolar lavage fluid and blood was collected, and markers of lung allergy and inflammation were assessed. An adjuvant effect of zymosan on OVA allergy during sensitization was observed as indicated by significant elevations in lung eosinophils, serum OVA-specific IgE, and lung IL-5 in the groups sensitized with zymosan and OVA. Pulmonary treatment with zymosan also amplified lung inflammation. Elevations were observed in lung neutrophils, TNF-α, and parameters of lung injury in the groups primed with both zymosan and OVA. In nearly all parameters, a non-linear dose-response relationship was observed in the groups primed with OVA and zymosan. The optimum adjuvant dose of zymosan was 10 µg. This study demonstrated an adjuvant effect of zymosan when exposures occurred during the sensitization phase in an OVA-induced allergy model in BALB/c mice.

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Section: Resultsmentioning

confidence: 99%

Adjuvant effect of zymosan after pulmonary treatment in a mouse ovalbumin allergy model

Young

Wolfarth

Roberts

et al. 2013

Experimental Lung Research

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“…IL-5 promotes the proliferation, migration, and survival of eosinophils during allergic airway inflammation (47). To determine whether IL-5 and IL-5-induced airway eosinophils were responsible for the decreased lung K. pneumoniae burden, we neutralized IL-5 during the course of our allergic airway inflammation-infection model using monoclonal anti-IL-5.…”

Section: Fig 5 Allergic Airway Inflammation Decreases K Pneumoniae-imentioning

confidence: 99%

Allergic Airway Inflammation Decreases Lung Bacterial Burden following Acute Klebsiella pneumoniae Infection in a Neutrophil- and CCL8-Dependent Manner

et al. 2014

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f The Th17 cytokines interleukin-17A (IL-17A), IL-17F, and IL-22 are critical for the lung immune response to a variety of bacterial pathogens, including Klebsiella pneumoniae. Th2 cytokine expression in the airways is a characteristic feature of asthma and allergic airway inflammation. The Th2 cytokines IL-4 and IL-13 diminish ex vivo and in vivo IL-17A protein expression by Th17 cells. To determine the effect of IL-4 and IL-13 on IL-17-dependent lung immune responses to acute bacterial infection, we developed a combined model in which allergic airway inflammation and lung IL-4 and IL-13 expression were induced by ovalbumin sensitization and challenge prior to acute lung infection with K. pneumoniae. We hypothesized that preexisting allergic airway inflammation decreases lung IL-17A expression and airway neutrophil recruitment in response to acute K. pneumoniae infection and thereby increases the lung K. pneumoniae burden. As hypothesized, we found that allergic airway inflammation decreased the number of K. pneumoniae-induced airway neutrophils and lung IL-17A, IL-17F, and IL-22 expression. Despite the marked reduction in postinfection airway neutrophilia and lung expression of Th17 cytokines, allergic airway inflammation significantly decreased the lung K. pneumoniae burden and postinfection mortality. We showed that the decreased lung K. pneumoniae burden was independent of IL-4, IL-5, and IL-17A and partially dependent on IL-13 and STAT6. Additionally, we demonstrated that the decreased lung K. pneumoniae burden associated with allergic airway inflammation was both neutrophil and CCL8 dependent. These findings suggest a novel role for CCL8 in lung antibacterial immunity against K. pneumoniae and suggest new mechanisms of orchestrating lung antibacterial immunity.

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“…IL-5 plays a key role in eosinophil proliferation, differentiation, maturation, migration to tissue sites and survival, as well as prevention of eosinophil apoptosis [5][6][7]. IL-5 comprises of a functional site for binding to the specific receptor subunit, IL-5Ra, and a separate motif for binding to the signalling subunit, b-chain [8]. The IL-5Ra subunit is specific only to IL-5 binding; the b-chain also binds the cytokines IL-3 and granulocyte-macrophage colony-stimulating factor via a shared extracellular domain [9].…”

Section: Introductionmentioning

confidence: 99%

Anti-interleukin-5 therapy in severe asthma

Garcia

Taillé

Laveneziana

et al. 2013

European Respiratory Review

112

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Asthma is a chronic inflammatory disorder of the airways that leads to acute symptoms, exacerbations and sometimes, for a small part of the asthmatic population, fatal or near-fatal exacerbations.This as yet significant minority of individuals present with severe asthma and have persisting daily symptoms, and exacerbations despite compliance with high doses of inhaled steroids and additional treatment. For more than a decade, the pharmacological management of patients with severe asthma has focused on evaluating specific cytokines. The rationale of this approach is based on the distinguished key role played by eosinophils in the asthma inflammatory processes. Eosinophils are recruited from the circulation to airways where they cause airway damage via different mechanisms. Eosinophils are regulated in terms of their recruitment, activation, growth, differentiation and survival by interleukin (IL)-5. Abundant data from in vitro experiments, animal models and clinical trials has confirmed that IL-5 inhibition may be an effective approach for the treatment of asthma, especially severe asthma. Interfering with eosinophil function or reducing their numbers has been one of the most important goals of therapeutic monoclonal antibodies, which target cytokine receptor interactions in asthma, particularly IL-5. This review will consider new treatments options for severe asthma, particularly those targeting IL-5, that have already been evaluated in clinical trials in asthmatic patients. @ERSpublications Rationale, recent advances and future developments of anti-IL-5 therapy in patients with severe asthma http://ow.ly/n3viv

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Molecular and clinical rationale for therapeutic targeting of interleukin‐5 and its receptor

Cited by 190 publications

References 243 publications

Adjuvant effect of zymosan after pulmonary treatment in a mouse ovalbumin allergy model

Adjuvant effect of zymosan after pulmonary treatment in a mouse ovalbumin allergy model

Allergic Airway Inflammation Decreases Lung Bacterial Burden following Acute Klebsiella pneumoniae Infection in a Neutrophil- and CCL8-Dependent Manner

Anti-interleukin-5 therapy in severe asthma

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