Therapeutic potential of anti-IL-6 therapies for granulocytic airway inflammation in asthma

Derek K. Chu, Amal Al-Garawi, Alba Llop-Guevara, Regina A. Pillai, Katherine Radford, Pamela Shen, Tina D. Walker, Susanna Goncharova, William Calhoun, Parameswaran Nair, Manel Jordana

Research output: Contribution to journalArticle

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Abstract

Background: Determining the cellular and molecular phenotypes of inflammation in asthma can identify patient populations that may best benefit from targeted therapies. Although elevated IL-6 and polymorphisms in IL-6 signalling are associated with lung dysfunction in asthma, it remains unknown if elevated IL-6 levels are associated with a specific cellular inflammatory phenotype, and how IL-6 blockade might impact such inflammatory responses. Methods: Patients undergoing exacerbations of asthma were phenotyped according to their airway inflammatory characteristics (normal cell count, eosinophilic, neutrophilic, mixed granulocytic), sputum cytokine profiles, and lung function. Mice were exposed to the common allergen, house dust-mite (HDM), in the presence or absence of endogenous IL-6. The intensity and nature of lung inflammation, and levels of pro-granulocytic cytokines and chemokines under these conditions were analyzed. Results: Elevated IL-6 was associated with a lower FEV<inf>1</inf> in patients with mixed eosinophilic-neutrophilic bronchitis. In mice, allergen exposure increased lung IL-6 and IL-6 was produced by dendritic cells and alveolar macrophages. Loss-of-function of IL-6 signalling (knockout or antibody-mediated neutralization) abrogated elevations of eosinophil and neutrophil recruiting cytokines/chemokines and allergen-induced airway inflammation in mice. Conclusions: We demonstrate the association of pleiotropic cellular airway inflammation with IL-6 using human and animal data. These data suggest that exacerbations of asthma, particularly those with a combined eosinophilic and neutrophilic bronchitis, may respond to therapies targeting the IL-6 pathway and therefore, provide a rational basis for initiation of clinical trials to evaluate this.

Original languageEnglish (US)
Article number14
JournalAllergy, Asthma and Clinical Immunology
Volume11
Issue number1
DOIs
StatePublished - Apr 12 2015

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Interleukin-6
Asthma
Inflammation
Therapeutics
Bronchitis
Cytokines
Chemokines
Lung
Allergens
Dermatophagoides Antigens
Phenotype
Alveolar Macrophages
Sputum
Eosinophils
Dendritic Cells
Pneumonia
Neutrophils
Cell Count
Clinical Trials
Antibodies

Keywords

  • Airway inflammation
  • Allergy
  • Asthma
  • Bronchitis
  • Eosinophil
  • Granulocyte
  • House dust-mite (HDM)
  • IL-6
  • IL-6R
  • Neutrophil

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Pulmonary and Respiratory Medicine

Cite this

Chu, D. K., Al-Garawi, A., Llop-Guevara, A., Pillai, R. A., Radford, K., Shen, P., ... Jordana, M. (2015). Therapeutic potential of anti-IL-6 therapies for granulocytic airway inflammation in asthma. Allergy, Asthma and Clinical Immunology, 11(1), [14]. https://doi.org/10.1186/s13223-015-0081-1

Therapeutic potential of anti-IL-6 therapies for granulocytic airway inflammation in asthma. / Chu, Derek K.; Al-Garawi, Amal; Llop-Guevara, Alba; Pillai, Regina A.; Radford, Katherine; Shen, Pamela; Walker, Tina D.; Goncharova, Susanna; Calhoun, William; Nair, Parameswaran; Jordana, Manel.

In: Allergy, Asthma and Clinical Immunology, Vol. 11, No. 1, 14, 12.04.2015.

Research output: Contribution to journalArticle

Chu, DK, Al-Garawi, A, Llop-Guevara, A, Pillai, RA, Radford, K, Shen, P, Walker, TD, Goncharova, S, Calhoun, W, Nair, P & Jordana, M 2015, 'Therapeutic potential of anti-IL-6 therapies for granulocytic airway inflammation in asthma', Allergy, Asthma and Clinical Immunology, vol. 11, no. 1, 14. https://doi.org/10.1186/s13223-015-0081-1
Chu, Derek K. ; Al-Garawi, Amal ; Llop-Guevara, Alba ; Pillai, Regina A. ; Radford, Katherine ; Shen, Pamela ; Walker, Tina D. ; Goncharova, Susanna ; Calhoun, William ; Nair, Parameswaran ; Jordana, Manel. / Therapeutic potential of anti-IL-6 therapies for granulocytic airway inflammation in asthma. In: Allergy, Asthma and Clinical Immunology. 2015 ; Vol. 11, No. 1.
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abstract = "Background: Determining the cellular and molecular phenotypes of inflammation in asthma can identify patient populations that may best benefit from targeted therapies. Although elevated IL-6 and polymorphisms in IL-6 signalling are associated with lung dysfunction in asthma, it remains unknown if elevated IL-6 levels are associated with a specific cellular inflammatory phenotype, and how IL-6 blockade might impact such inflammatory responses. Methods: Patients undergoing exacerbations of asthma were phenotyped according to their airway inflammatory characteristics (normal cell count, eosinophilic, neutrophilic, mixed granulocytic), sputum cytokine profiles, and lung function. Mice were exposed to the common allergen, house dust-mite (HDM), in the presence or absence of endogenous IL-6. The intensity and nature of lung inflammation, and levels of pro-granulocytic cytokines and chemokines under these conditions were analyzed. Results: Elevated IL-6 was associated with a lower FEV1 in patients with mixed eosinophilic-neutrophilic bronchitis. In mice, allergen exposure increased lung IL-6 and IL-6 was produced by dendritic cells and alveolar macrophages. Loss-of-function of IL-6 signalling (knockout or antibody-mediated neutralization) abrogated elevations of eosinophil and neutrophil recruiting cytokines/chemokines and allergen-induced airway inflammation in mice. Conclusions: We demonstrate the association of pleiotropic cellular airway inflammation with IL-6 using human and animal data. These data suggest that exacerbations of asthma, particularly those with a combined eosinophilic and neutrophilic bronchitis, may respond to therapies targeting the IL-6 pathway and therefore, provide a rational basis for initiation of clinical trials to evaluate this.",
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AU - Radford, Katherine

AU - Shen, Pamela

AU - Walker, Tina D.

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AB - Background: Determining the cellular and molecular phenotypes of inflammation in asthma can identify patient populations that may best benefit from targeted therapies. Although elevated IL-6 and polymorphisms in IL-6 signalling are associated with lung dysfunction in asthma, it remains unknown if elevated IL-6 levels are associated with a specific cellular inflammatory phenotype, and how IL-6 blockade might impact such inflammatory responses. Methods: Patients undergoing exacerbations of asthma were phenotyped according to their airway inflammatory characteristics (normal cell count, eosinophilic, neutrophilic, mixed granulocytic), sputum cytokine profiles, and lung function. Mice were exposed to the common allergen, house dust-mite (HDM), in the presence or absence of endogenous IL-6. The intensity and nature of lung inflammation, and levels of pro-granulocytic cytokines and chemokines under these conditions were analyzed. Results: Elevated IL-6 was associated with a lower FEV1 in patients with mixed eosinophilic-neutrophilic bronchitis. In mice, allergen exposure increased lung IL-6 and IL-6 was produced by dendritic cells and alveolar macrophages. Loss-of-function of IL-6 signalling (knockout or antibody-mediated neutralization) abrogated elevations of eosinophil and neutrophil recruiting cytokines/chemokines and allergen-induced airway inflammation in mice. Conclusions: We demonstrate the association of pleiotropic cellular airway inflammation with IL-6 using human and animal data. These data suggest that exacerbations of asthma, particularly those with a combined eosinophilic and neutrophilic bronchitis, may respond to therapies targeting the IL-6 pathway and therefore, provide a rational basis for initiation of clinical trials to evaluate this.

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KW - IL-6R

KW - Neutrophil

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