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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI023521-04
Application #
3135750
Study Section
Pathology A Study Section (PTHA)
Project Start
1986-12-01
Project End
1994-11-30
Budget Start
1989-12-01
Budget End
1990-11-30
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Neelamegham, S; Taylor, A D; Burns, A R et al. (1998) Hydrodynamic shear shows distinct roles for LFA-1 and Mac-1 in neutrophil adhesion to intercellular adhesion molecule-1. Blood 92:1626-38
Juneja, H S; Schmalstieg, F C; Lee, S et al. (1998) CD45 partially mediates heterotypic adhesion between murine leukemia/lymphoma cell line L5178Y and marrow stromal cells. Leuk Res 22:805-15
Neelamegham, S; Taylor, A D; Hellums, J D et al. (1997) Modeling the reversible kinetics of neutrophil aggregation under hydrodynamic shear. Biophys J 72:1527-40
Perez, R G; Arai, M; Richardson, C et al. (1996) Factors modifying protective effect of anti-CD18 antibodies on myocardial reperfusion injury in dogs. Am J Physiol 270:H53-64
Mickelson, J K; Lakkis, N M; Villarreal-Levy, G et al. (1996) Leukocyte activation with platelet adhesion after coronary angioplasty: a mechanism for recurrent disease? J Am Coll Cardiol 28:345-53
Davis, S L; Hawkins, E P; Mason Jr, E O et al. (1996) Host defenses against disseminated candidiasis are impaired in intercellular adhesion molecule 1-deficient mice. J Infect Dis 174:435-9
Taylor, A D; Neelamegham, S; Hellums, J D et al. (1996) Molecular dynamics of the transition from L-selectin- to beta 2-integrin-dependent neutrophil adhesion under defined hydrodynamic shear. Biophys J 71:3488-500
Kukielka, G L; Smith, C W; LaRosa, G J et al. (1995) Interleukin-8 gene induction in the myocardium after ischemia and reperfusion in vivo. J Clin Invest 95:89-103
Wakefield, T W; Strieter, R M; Wilke, C A et al. (1995) Venous thrombosis-associated inflammation and attenuation with neutralizing antibodies to cytokines and adhesion molecules. Arterioscler Thromb Vasc Biol 15:258-68
Keeney, S E; Mathews, M J; Haque, A K et al. (1995) Comparison of pulmonary neutrophils in the adult and neonatal rat after hyperoxia. Pediatr Res 38:857-63

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