ROLE OF LFA-1/MAC-1/P150, 95 IN PMN LEUKOCYTE ADHERENCE

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The biologic importance of leukocyte adherence proteins Mac-1 (CDllb/CD18), LFA-1 (CDlla/CD18) and p150,95 (CDllc/CD18) has been underscored by the discovery and characterization of patients genetically deficient in expression of these proteins (Leukocyte Adhesion Deficiency or LAD), the recognition that these proteins are related to other integrins recognizing extracellular matrix (ECM) proteins, and the identification of intercellular adherence molecule-1 (ICAM-1) and its characterization as a ligand for LFA-1. The studies in this proposal will address three general issues: 1) The major ligands for Mac-1-dependent adhesion to cellular surfaces and extracellular matrix proteins have not been defined. While recent evidence indicates that ICAM-1 may be a ligand for Mac-1, Mac-1 appears to be able to interact with a variety of other structures. One hypothesis is that a common molecular mechanism underlies these interactions. In addition to the specific binding sites, quantitative and/or qualitative changes in Mac-1 on the neutrophil's surface appear to accompany chemotactic stimulation, and may necessarily precede interaction of Mac-1 with its ligand. Efforts to identify the possible ligands and binding sites, and evaluate the role of quantitative and qualitative changes in surface Mac-1 will involve the production and use of monoclonal antibodies and synthetic peptides in studies of homotypic aggregation, adherence of neutrophil to endothelial cells, ECM proteins (fibronectin,l laminin, collagen types I and IV), and protein-coated surfaces (fibrogen and keyhole limpet hemocyanin). 2) The contribution of Mac-1 to some specific neutrophil functions (homotypic aggregation, adherence to albumin- coated glass and plastic, binding of iC3b-coated particles) has been demonstrated. Its role in attachment endothelial cells and ECM proteins, transendothelial migration, and secretion of granule contents have reactive oxygen, and the possible cooperation of Mac-1 and other adhesive molecules in these functions have not been defined. Efforts to evaluate additional functional roles for Mac-1 will utilize specific monoclonal antibodies reactive with each of the subunits of the CD18 family and a newly described neutrophil fibronectin receptor (leukocyte response integrin) in studies of adhesion, migratory, secretory and cytotoxic functions. 3) The role of ICAM-1 in acute inflammation has not been defined. Recent evidence indicates that CD18-dependent adhesion of neutrophils to endothelial cells involves ICAM-1. Efforts to evaluate such a role for ICAM-1 will utilize a lapine model of acute inflammation. This will require cloning and sequencing lapine ICAM(s) and the development of defined monoclonal antibodies reactive with lapine ICAM. Information derived from these investigations should provide definition of molecular determinants and regulatory mechanisms of leukocyte adhesion, and should lead directly to evaluations of anti-adherence strategies in the regulation of inflammation.