This project incorporates studies on immunologic and cellular events during induction of IgE mediated airway responses in rhesus monkeys by ascaris infestation. The current colony of asthmatic monkeys will be maintained and antigen induced airway responses compared to responses induced by metabolites of arachidonic acid such as leukotrienes C4, D4, E4. Inhibitors of phospholipase A, which releases arachidonic acid, will be evaluated as inhibitors of primate antigen induced asthma. Inhibitors of the lipoxygenase metabolic pathway of arachidonic acid metabolism which would inhibit production of leukotrienes will be evaluated as inhibitors of asthma. Finally, antagonists of leukotrienes will be analyzed as they are made available. Other potential therapeutic agents for asthma will be studied as they are evolved in other laboratories. This primate model of asthma will thus be used to evaluate basic immunologic mechanisms and as a pharmacologic model for inhibition of primate asthma as a step in evolution of therapeutic agents for human IgE mediated asthma. Occupational immunologic lung diseases of several types have been described and immunologic correlations made using 3 chemical-protein conjugates. Serial studies can be done in workers but frequent studies, sequential bronchial challenge and evaluation of possible mechanisms are difficult to carry out, particularly at distant plant sites. For these reasons, animal models of trimellitic anhydride (TMA), diphenylmethane diisocyanate (MDI) and toluence diisocyanate (TDI) are being established. Dogs are utilized as a large animal suitable for repeated pulmonary function studies and because they make IgE antibody against inhaled antigens. Preliminary studies indicate that dogs can be used as models of TMA, MDI and TDI pulmonary disease. These models will be expanded and correlations of various immunologic and bronchial challenge responses made. Local pulmonary response to inhaled haptens will be measured and correlated with systemic responses and studies of methods of control of antibody responses will be initiated.
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