Leukocyte migration through vascular endothelium at sites of injury is the central event in the inflammatory response. Soluble mediators known as chemoattractants activate leukocytes and direct their migration through the vessel wall. While several of the chemoattractants which recruit neutrophils and monocytes have been identified and characterized, little is known about lymphocyte chemoattractants. Based on the behavior of specific lymphocyte subsets in immune surveillance and inflammation, we hypothesize that at least two different lymphocyte chemoattractants exist. The goals of our proposed research are to identify and purify human lymphocyte chemoattractants, to characterize their structure and function, and to study the mechanisms by which they activate lymphocyte binding and migration. Our strategy for identifying these molecules involves screening likely sources using lymphocyte chemotaxis assays and binding assays which detect changes in the binding of integrin adhesion molecules on the lymphocyte surface. We expect to identify multiple small proteins; our strategy for characterization will begin with purification and progress to functional studies, monoclonal antibody production, and complementary DNA isolation and sequence analysis. The identification and characterization of these molecules should help define the molecular mechanisms of lymphocyte migration, and provide new targets for the therapy of chronic inflammatory diseases.
