The work proposed is aimed at the dissection of cellular effector mechanisms leading to chronic immunologic lung injury, with specific attention to the immunopathogenesis of hypersensitivity interstitial lung disease. Established rabbit models to be utilized include chronic hypersensitivity pneumonitis, desensitization, and immunosuppression produced respectively by repeated inhalation of antigen and muramyl dipeptide, antigen alone, or concurrent administration of cyclosporine. Methods involve primarily those of experimental pathology and cellular immunology. Specific objectives are to 1) explore in vivo and in vitro cellular participation, functional changes and cellular responses to antigen and to the adjuvant muramyl dipeptide and various congeners which result in a postulated necessary two-signal system leading to inflammation of the lung parenchyma; 2) identification of effector T cell subsets mediating inflammation using available and to-be-developed monoclonal antibodies; 3) identification of receptors for muramyl dipeptide and various congeners on effector cells of inflammation; and 4) preliminary explorations of the feasibility of using identical monozygotic rabbit littermates for studies of in vivo passive transfer and in vitro cellular interactions including immunosuppression in definitive dissection of cellular mechanisms of immunologic lung injury. The pathogenesis of hypersensitivity pneumonitis remains to be completely defined, and the proposed studies should help clarify hypersensitivity mechanisms leading to interstitial lung disease in general, with implications for prevention, diagnosis and treatment of human lung disease.
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