Blocking IL-25 prevents airway hyperresponsiveness in allergic asthma.
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.


CONCLUSIONS
IL-25 is critical for development of AHR.


CONCLUSIONS
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.
Ballantyne
Sarah J
SJ
Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.
Barlow
Jillian L
JL
Jolin
Helen E
HE
Nath
Puneeta
P
Williams
Alison S
AS
Chung
Kian Fan
KF
Sturton
Graham
G
Wong
See Heng
SH
McKenzie
Andrew N J
AN
D000818:Animals; D019138:Antibodies, Blocking / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001249:Asthma / Q000276:immunology* / Q000503:physiopathology / Q000628:therapy*; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D018793:Interleukin-13 / Q000378:metabolism; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000276:immunology
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; C486701:IL25 protein, human; D018793:Interleukin-13; D020381:Interleukin-17