Mechanisms of asthma and allergic inflammation
Blocking IL-25 prevents airway hyperresponsiveness in allergic asthma

https://doi.org/10.1016/j.jaci.2007.07.051Get rights and content

Background

IL-25 (IL-17E), a member of the IL-17 family of immunoregulatory cytokines, has been implicated in the regulation of type 2 immunity. Its roles in antigen-driven airway inflammation and airway hyperresponsiveness (AHR) remain to be fully established.

Objective

We sought to determine whether a neutralizing antibody against IL-25 represents a novel therapeutic for airway inflammation and hyperresponsiveness.

Methods

We generated a neutralizing mAb against IL-25 and used this to inhibit IL-25 in a mouse model of allergic airway disease.

Results

Blocking IL-25 in an experimental model of allergic asthma prevented AHR, a critical feature of clinical asthma. Administration of anti–IL-25 mAb during the sensitization phase resulted in significantly reduced levels of IL-5 and IL-13 production, eosinophil infiltration, goblet cell hyperplasia, and serum IgE secretion, and prevented AHR. Even more striking was the ability of anti–IL-25 mAb, administered only during the challenge phase of the response, specifically to prevent AHR even during an ongoing type 2 inflammatory response in the lungs.

Conclusion

IL-25 is critical for development of AHR.

Clinical implications

We define a novel pathway for the induction of AHR and suggest that IL-25 represents an important therapeutic target for the treatment of asthma. Significantly, our antibody also blocks the binding of human IL-25 to its receptor.

Section snippets

Mice

BALB/c mice were obtained from Harlan UK (Bicester, UK) and maintained in the Small Animal Barrier Unit and Central Biomedical Services or National Heart and Lung Institute facilities in specific pathogen-free environments. il4–/–il5–/–il9–/–il13–/– mice and il13–/– mice on a BALB/c background (6th generation backcross) were as described.1, 16Il25–/– mice on a C57BL/6 × 129 background were as described.11 All animal experiments outlined in this report were undertaken with the approval of the UK

Generation of blocking anti–rmIL-25 mAbs

To study the biology of IL-25, we generated anti–IL-25 mAbs by immunizing il25–/– mice with rmIL-25. Two of these anti–IL-25 antibodies (2C3 and 5C1) blocked the interaction between rmIL-25 and a soluble mouse IL-25R-Fc fusion protein dose-dependently (data not shown) and inhibited IL-25–dependent production of IL-13 by primary mouse non-B, non-T cells in an in vitro bioassay (data not shown).

Neutralization of IL-25 during sensitization and airway challenge prevents development of allergic airway inflammation and AHR

Our studies and those of others suggest that IL-25 acts upstream of the type 2 cytokines and that by

Discussion

Using an antagonist of IL-25 to block IL-25 bioactivity, our data highlight for the first time the critical and functionally distinct roles played by endogenous IL-25 in a mouse model of allergic asthma. We have shown that IL-25 acts first at the initiation of the type 2 cytokine–dependent induction of airway inflammation, but also plays an essential role in the development of AHR independently of the inflammatory response, through both IL-13–dependent and independent pathways.

When administered

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      IL-25 can augment downstream T2 cytokine expansion, including IL-4, IL-5 and IL-13, and increase IgE level and eosinophil count. IL-25 inhibition in mouse models of allergic asthma diminishes recruitment of eosinophils and other TH2-polarizing cells to the airway and abrogates IL-5, IL-13, and IgE levels and AHR.90 Like the effects of TSLP, these IL-25 effects have the potential to regulate T2-dependent asthma.

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    Supported by a grant from the Medical Research Council of Great Britain and Asthma UK.

    Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

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