| Summary: | <i>I125<sup>-/-</sup></i> animals, generated in the laboratory, were used to assess the role of IL-25 during initiation of immune responses. Expulsion of <i>Nippostrongylus brasiliensis, </i>an intestinal parasite, has been shown to be critically dependent on rapid production of the type-2 cytokines IL-4 and IL-13. IL-25 deficient animals failed to expel <i>N. brasiliensis </i>efficiently and this correlated with a delay in type-2 cytokine production. Conversely, administration of exogenous IL-25 induced a rapid parasite expulsion that was independent of T or B cells but required type-2 cytokine expression. Analysis of the draining (mesenteric) lymph nodes by flow cytometry revealed a novel non-B/non-T, c-kit<sup>+</sup>, FcεR1<sup>-</sup> cell population induced following infection of wildtype animals but absent in the lymph nodes of infected <i>il25<sup>-/-</sup></i> mice. This population, which was also induced following administration of recombinant IL-25 protein, expressed IL-4 and IL-13 mRNA. These data clearly demonstrate the critical role IL-25 plays during initiation of protective Th2 responses. To investigate whether IL-25 also plays a role in atopic disease, a neutralising anti-IL-25 antibody was generated and then assessed in a murine model of allergic airway disease. This protocol replicates the major features found in human asthma including airway hyperresponsiveness (AHR). Administration of anti-IL-25 blocking antibody prior to sensitisation and pulmonary challenge completely abrogated airway inflammation and AHR. Significantly, when pre-sensitised animals were treated with anti-IL-25 antibody only during antigen challenge in the lung, AHR was still blocked. IL-25 regulates airway inflammation and AHR partially by modulating local levels of IL-13 and IL-17; indeed the inhibitory effects of anti-IL-25 antibody were reversed by co-administration of a neutralising anti-IL-17 antibody. However, analysis of mice deficient in IL-4, IL-5, IL-9 and IL-13 suggest that IL-25 can also modulate AHR via a type-2 cytokine independent mechanism.
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