INTERLEUKIN-12 INHIBITS ANTIGEN-INDUCED AIRWAY HYPERRESPONSIVENESS, INFLAMMATION, AND TH2 CYTOKINE EXPRESSION IN MICE

Allergic asthma is characterized by ah-way hyperresponsiveness and pul monary eosinophilia, and may be mediated by T helper (Th) lymphocytes expressing a Th2 cytokine pattern. Interleukin (IL) 12 suppresses the expression of Th2 cytokines and their associated responses, including eosinophilia, serum immunoglobulin E, and mucosal mastocytosis. We hav e previously shown in a murine model that antigen-induced increases in airway hyperresponsiveness and pulmonary eosinophilia are CD4(+) T ce ll dependent. We used this model to determine the ability of IL-12 to prevent antigen-induced increases in airway hyperresponsiveness, bronc hoalveolar lavage (BAL) eosinophils, and lung Th2 cytokine expression. Sensitized A/J mice developed airway hyperresponsiveness and increase d numbers of BAL eosinophils and other inflammatory cells after single or repeated intratracheal challenges with sheep red blood cell antige n. Pulmonary mRNA and protein levels of the Th2 cytokines IL-I and IL- 5 were increased after antigen challenge. Administration of IL-12 (1 m u g/d X 5 d) at the time of a single antigen challenge abolished the a irway hyperresponsiveness and pulmonary eosinophilia and promoted an i ncrease in interferon (IFN) gamma and decreases in IL-4 and IL-5 expre ssion. The effects of IL-12 were partially dependent on IFN-gamma, bec ause concurrent treatment with IL-12 and anti-IFN-gamma monoclonal ant ibody partially reversed the inhibition of airway hyperresponsiveness and eosinophilia by IL-12. Treatment of mice with IL-12 at the time of a second antigen challenge also prevented airway hyperresponsiveness and significantly reduced numbers of BAL inflammatory cells, reflectin g the ability of IL-12 to inhibit responses associated With Ongoing an tigen-induced pulmonary inflammation. These data show that antigen-ind uced airway hyperresponsiveness and inflammation can be blocked by IL- 12, which suppresses Th2 cytokine expression. Local administration of IL-12 may provide a novel immunotherapy for the treatment of pulmonary allergic disorders such as atopic asthma.