IL-25 as a potential therapeutic target in allergic asthma

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Date: July 2015
From: Immunotherapy(Vol. 7, Issue 6)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 2,398 words
Lexile Measure: 1990L

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Author(s): Martin D Knolle [*] aff1 aff2 , Batika M Rana aff1 , Andrew NJ McKenzie aff1


allergy; asthma; innate lymphoid cells; interleukin-25; viral exacerbation

Allergic asthma is a prevalent disease characterized by intermittent airway hyper-responsiveness resulting in airway narrowing, debilitating wheezing and shortness of breath that in severe cases can prove fatal. Notably, the number of sufferers, especially among children, has increased dramatically over recent decades and the WHO estimates that 235 million people worldwide suffer from this disorder. Asthma can be induced by a variety of provocative allergic stimuli and is associated with pulmonary inflammatory infiltrates including T helper 2 (Th2) cells and type-2 innate lymphoid cells (ILC2s) secreting the type-2 cytokines IL-4, IL-5 IL-9 and IL-13. These cytokines co-ordinate the inappropriate muscular contraction, immunoglobulin E production, eosinophilia and mucus hypersecretion that typify asthma.

Despite being characterized for over a century, asthma is often underdiagnosed and there have been few therapeutic advances since the introduction of steroids in the 1950s (e.g., antileukotrienes and anti-IgE treatment). In part, this is due to the complexity of the disease with the existence of subtypes of asthma only now being fully realized. These recent improvements in our understanding have resulted in clinical trials establishing the potential of biological asthma treatments such as antibodies that neutralize IL-5 and IL-13. However, these therapies only work in subsets of asthma patients, leading to an unmet need for additional novel treatments.

A triad of lung epithelium-derived cytokines, IL-25, IL-33 and thymic stromal lymphopoietin (TSLP), that lie upstream of the effector type-2 cytokines, have emerged as important mediators in asthma and are therefore potential treatment targets [1 ]. IL-25 was identified in 2001 and found to induce type-2 immune responses in human and animal studies [2 ]. It is a member of the IL-17 cytokine family and in contrast to IL-17A elicits type-2 cytokine production via its receptor IL17 receptor beta (IL-17RB, IL-25R) [3 ]. Although IL-25 is reported to be expressed by a range of structural (including bronchial epithelial cells and endothelial cells) and immune cells (Th cells, macrophages, dendritic cells, basophils and mast cells), it is generally difficult to detect IL-25 protein, presumably because it is produced in low amounts or consumed rapidly. Thus, the cellular sources of IL-25 and the mechanisms by which it is released during disease still remain unclear. A range of immune cells are responsive to IL-25, such as Th2 and Th9 cells, ILC2, monocytes, eosinophils and natural killer T cells; all of which have been shown to contribute to asthma pathogenesis.

Mouse models have indicated that IL-25 may represent an important target in asthma, for example, administration of IL-25 into mouse lungs reproduces many features of allergic airway inflammation. Furthermore, neutralization of IL-25 during ovalbumin sensitization and challenge of the lung reduced goblet cell hyperplasia, eosinophilia, IgE, IL-5 and IL-13 production. Importantly, blocking IL-25 also decreased pulmonary resistance in these studies [ 4 ]. Similarly, cockroach allergen significantly increased IL-25-induced pulmonary inflammation that was abrogated in IL-25 receptor-deficient ( Il17br-/- ) mice...

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Gale Document Number: GALE|A422428338