Asthma is a complex disease believed to reflect aberrant immune responsiveness to environmental antigens encountered through the airway. Various hypotheses that link Th2-type responses with lung pathology have been proposed for asthma, but human studies remain correlative at this time. A mouse model of airway reactivity to aerosolized antigens has been established that will permit delineation of the critical pathways by which airway physiologic and immunologic responses become established and are mediated. This model, involving sensitization of animals to ovalbumin, has identified crucial requirements for CD4+ T cells and interleukin (IL)- 4 during the initial exposure to antigen. We propose to use specific reagents and knock-out animals with defined absence of various immune molecules to probe molecular events underlying the differentiation of effector T cells required for the induction of airway reactivity and the effector pathways that mediate airway reactivity. In a series of four interrelated aims, we will (1) establish the kinetics for IL-4 requirements during priming and elucidate the source of IL-4 required for the development of pathology-inducing T cells; (2) delineate requirements for costimulation through the CD28-B7 and CD40-CD40L ligand systems; (3) test the ability to abrogate pathologic responses by bypassing requisite costimulatory pathways using altered T cell receptor ligands; and (4) use MHC class II-restricted T cell receptor transgenic mice on two different genetic backgrounds that produce differing amounts of IL-4 during priming in order to test hypotheses generated in the prior aims using wild-type mice. Establishing models for airway hyperreactivity in transgenic TCR mice will be important in defining systems in which greater numbers of reactive T cells can be generated for experimental purposes and in beginning to analyze the influence of genetic predisposition on the development of immunopathologic lung disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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University of California San Francisco
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