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Targeting cytokines to treat asthma and chronic obstructive pulmonary disease

Nature Reviews Immunology volume 18, pages 454–466 (2018)Cite this article

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Abstract

Cytokines play a key role in orchestrating and perpetuating the chronic airway inflammation in asthma and chronic obstructive pulmonary disease (COPD), making them attractive targets for treating these disorders. Asthma and some cases of COPD are mainly driven by type 2 immune responses, which comprise increased airway eosinophils, T helper 2 (TH2) cells and group 2 innate lymphoid cells (ILC2s) and the secretion of IL-4, IL-5 and IL-13. Clinical trials of antibodies that block these interleukins have shown reduced acute exacerbations and oral corticosteroid use and improvements in lung function and symptoms in selected patients. More recent approaches that block upstream cytokines, such as thymic stromal lymphopoietin (TSLP), show promise in improving patient outcome. Importantly, the clinical trials in cytokine blockade have highlighted the crucial importance of patient selection for the successful use of these expensive therapies and the need for biomarkers to better predict drug responses.

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Fig. 1: Targeting type 2 cytokines in airway disease.
Fig. 2: Targeting non-type 2 immunity in airway disease.

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Acknowledgements

P.J.B. holds a National Institute for Health Research Senior Investigator Award.

Competing interests

P.J.B. has served on Scientific Advisory Boards of AstraZeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Glenmark, Johnson & Johnson, Napp, Novartis, Pfizer, ProSonix, RespiVert, Teva and Zambon and has received research funding from AstraZeneca, Boehringer-Ingelheim, Chiesi, Novartis and Takeda.

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Nature Reviews Immunology thanks Sally Wenzel and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Airway Disease Section, National Heart and Lung Institute, Imperial College, London, UK

    Peter J. Barnes

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Glossary

U-BIOPRED

Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes is a European project investigating mechanisms of severe asthma.

Type 2 immunity

A type of immunity that provides protection against parasitic infections but is also activated in allergic diseases such as asthma. It is orchestrated by T helper 2 (TH2) cells and group 2 innate lymphoid cells (ILC2s) through the secretion of IL-4, IL-5, IL-9 and IL-13, which are regulated by the transcription factor GATA3. Type 2 inflammation is characterized by eosinophils, mast cells and alternatively activated macrophages. Upstream cytokines from epithelial cells that regulate TH2 cells and ILC2s include the alarmins IL-25, IL-33 and thymic stromal lymphopoietin (TSLP).

T helper 2 (TH2) cells

A subset of CD4+ T helper cells that has an important role in humoral immunity and in allergic responses. TH2 cells express the transcription factors GATA3 and signal transducer and activator of transcription 6 (STAT6) and produce cytokines such as IL-4, IL-5, IL-9 and IL-13, which regulate IgE synthesis, eosinophil proliferation, mast cell proliferation and airway hyperresponsiveness, respectively.

Innate lymphoid cells

Immune cells that do not express antigen specific B or T cell receptors. Three main subtypes are recognized depending on the transcription factors expressed and the pattern of cytokines they release.

Airway hyperresponsiveness

Increased airway narrowing in response to various external stimuli that is a physiological characteristic of patients with asthma.

Type 1 immunity

A type of immunity that provides protection against microbial infections and is orchestrated by T helper 1 cells, cytotoxic T cells and group 1 innate lymphoid cells and the transcription factor T-bet, which regulates the secretion of IFNγ. Type 1 immunity is associated with increased pro-inflammatory macrophage activation.

Type 3 immunity

A type of immunity that is directed against microorganisms, in particular fungi, and orchestrated by T helper 17 cells and group 3 innate lymphoid cells, which express RORγt and secrete IL-17 and IL-22, leading to neutrophilic inflammation.

TH17 cells

A subset of CD4+ T helper cells that express the transcription factor RORγt and secrete IL-17A, IL-17F and IL-22. They are involved in neutrophilic inflammatory responses and are important in responses to bacteria and viruses, as well as autoimmune diseases.

GATA3

A transcription factor expressed predominantly by T helper 2 cells and group 2 innate lymphoid cells that is important for their differentiation and secretion of characteristic type 2 cytokines (IL-4, IL-5, IL-9 and IL-13).

Forced expired volume in 1 second

(FEV1). A measure of airflow. Decreases in FEV1 reflect airway obstruction in asthma and chronic obstructive pulmonary disease and are a measure of disease severity.

Fractional exhaled nitric oxide

(FeNO). The fractional content in exhaled breath of nitric oxide gas, which is a non-invasive biomarker of type 2 inflammation.

Alarmin

A type of molecule that is released from damaged cells and activates the immune system. In airway disease, alarmins released from airway epithelial cells include IL-25, IL-33 and thymic stromal lymphopoietin (TSLP), which activate type 2 immunity.

NLRP3 inflammasome

Intracellular multiprotein complex containing NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), which leads to activation of caspase 1 and the generation of IL-1β and IL-18 from precursors. It is a component of the innate immune system and activated by several inflammatory signals.

Muckle–Wells syndrome

Rare autosomal dominant disease that causes periodic fever and is associated with NLRP3 inflammasome activation and increased production of IL-1β.

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Barnes, P.J. Targeting cytokines to treat asthma and chronic obstructive pulmonary disease. Nat Rev Immunol 18, 454–466 (2018). https://doi.org/10.1038/s41577-018-0006-6

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