Lymphocytes are believed to play important roles in the pathogenesis of various lung diseases, including many of the pulmonary complications of rheumatologic disorders. The long-term objective of this project is to explain the molecular basis of lymphocyte recruitment to the lung. In recent years, lymphocyte adhesion molecules and corresponding endothelial cell ligands responsible for directing the selective recruitment (or """"""""homing"""""""") of lymphocytes to peripheral lymph node, skin, and gut have been identified. Previous work and our preliminary studies suggest that some lymphocytes home to the lung. The proposed study is designed to identify lymphocyte subsets that are preferentially recruited to the normal and antigen-stimulated sheep lung, and to identify lymphocyte adhesion molecules and other surface proteins that may play a role in this process. To compare recirculation of lymphocytes from lung, gut, and peripheral node lymph (Aim 1), efferent lymph will be obtained by cannulation of individual lymphastics. Fluorescently-labeled lymphocytes will be reinjected intravenously and their migration into lung and other tissues will be measured. To determine the effect of antigen stimulation (Aim 2), recruitment of lymphocytes and lymphoblasts will be analyzed after intrabronchial administration of horse red blood cells. To identify differences in the expression of adhesion molecules and other surfaces molecules on lymphocytes from lung, gut, and peripheral lymph (Aim 3), these lymphocytes will be analyzed by three-color flow cytometry and by two-dimensional protein gel electrophoresis. These experiments will identify lymphocytes that are selectively recruited to the lung and specific molecules that might mediate lung homing. In future experiments, blocking monoclonal antibodies will be used in the sheep system to establish the role of each specific molecule. An understanding of the molecular basis of lymphocyte recruitment to the lung will allow for the design of therapeutic strategies for manipulating the pulmonary immune response and for selectively delivering drugs to the lung.
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