CYTOKINE MANIPULATION IN ANIMAL-MODELS OF ASTHMA

We have developed in C57 Black 6 mice an in vivo model of allergic air way inflammation characterized by the presence of IgE antibodies to an inhaled antigen, peribronchial infiltrates with an increased number o f eosinophils, and an increased airway responsiveness to nonantigenic bronchoconstrictor stimuli. In this animal model we have investigated the role of different cytokines in the development of IgE antibodies t o inhaled antigen, eosinophilic airway inflammation, and airway hyperr esponsiveness. The studies were performed by using knockout mice or by exogenous administration of cytokines or cytokine antagonists. Interl eukin-4 (IL-4) knockout mice were unable to develop an allergic eosino philic airway infiltration and did not produce specific IgE antibodies . Chronic aerosol exposure to antigen also did not induce an increase in airway responsiveness. In studies of wildtype mice, pretreatment wi th the combination of anti-IL5 and anti-IL5 receptor antibodies, given in an attempt to fully inhibit the effect of endogenously released IL -5, caused a pronounced inhibition of the antigen-induced airway eosin ophilia but did not prevent the increase in airway responsiveness. Tre atment with IL-12 during the active immunization prevented airway eosi nophilia, production of specific IgE antibodies, and the antigen-induc ed increase in airway responsiveness. In contrast, administration of I L-12 to actively immunized mice during the aerosol exposure abolished airway eosinophilia and airway hyperresponsiveness without affecting t he production of specific IgE.