Cytokines and Cytokine-Specific Therapy in Asthma

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Abstract

Asthma is increasing in prevalence worldwide. It is characterized by typical symptoms and variable airway obstruction punctuated with episodes of worsening symptoms known as exacerbations. Underlying this clinical expression of disease is airway inflammation and remodeling. Cytokines and their networks are implicated in the innate and adaptive immune responses driving airway inflammation in asthma and are modulated by host–environment interactions. Asthma is a complex heterogeneous disease, and

Cytokines

The generic term cytokine was coined a few years after the discovery in the late 1960s of lymphocyte-activating factor (LAF) which proved that macrophages released a mitogenic factor that promoted T-cell proliferation in the absence of other growth factors or antigens. More cytokines are discovered as the field of immunology expands. Cytokines include the interleukin, chemokines, and growth factor families (as described in Table 1). There is structural homology across groups of cytokines

Cytokine-Directed Therapy in Asthma

The complexity of cytokine networks described above suggests that cytokine-specific therapy is likely to be challenging with substantial redundancy in biological pathways. However, there has been much interest in dissecting the relative role of key cytokines described below. This has led to, and is informed by, early clinical trials of cytokine-specific therapy summarized in Table 6. These studies have been pivotal in furthering our understanding of the role of cytokines in asthma and are

TNF-α and Its Role in Severe Asthma

A number of animal model and human studies have implicated the role of TNF-α in airways disease including asthma, chronic obstructive pulmonary disease (COPD), and interstitial lung disease. Rheumatoid arthritis and inflammatory bowel disease are other examples of chronic disease where TNF-α has a major part to play in their pathophysiology, and treatment with anti-TNF therapy either by neutralizing antibodies or receptor blockade leads to an improvement in many indices of disease activity [182]

Interferons

Interferons (IFN) are a super family of structurally related cytokines with immunomodulatory and antiviral properties. Type I family includes IFN-α,-β,-ω,-κ, and-ε with the sole member of type II family being IFN-γ. The type III family consists of IFN-λ1, IFN-λ2, and IFN-λ3, also called IL-29, IL-28A, and IL-28B, respectively [205], [206]. The types I and III family signal through a receptor IFN-αR whereas IFN-γ signals via IFN-γR. The downstream effects of receptor ligand interaction are

Interleukin-17

The family (IL-17A-F) of cytokines are linked with several autoimmune diseases such as RA, IBD, and multiple sclerosis; in particular, IL-17E and F are of interest in asthma as expression is increased the airway of asthmatic patients and correlated with disease severity [216]. Animal models have demonstrated that IL-17 induces inflammatory Th2 cytokines like IL-1, 6, 21 and TNF, chemokines CXCL1, 2, inflammatory cells (eosinophils and neutrophils), and AHR [217], [218], [219]. The effects may

Conclusions

Asthma is a complex heterogeneous condition. The cytokine networks in asthma demonstrate that several biological processes can both result in apparently similar or distinct clinical expression and thus present the challenge of both redundancies in the system but also knowing which pathway is relevant in which patient. Importantly, lessons from current cytokine-specific therapy have not only highlighted the need to consider the patients’ biological phenotype and the appropriate outcome measure

Acknowledgment

CB is funded by a Wellcome Senior Clinical Fellowship.

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