The regulation of leukocyte adhesion to endothelial cells is an essential and complex aspect of leukocyte migration and metastasis. The ability of leukocytes to home to, or localize in, areas of inflammation is also critical for the generation of a rapid immune response. This study will examine the molecules which mediate the interactions between leukocytes and endothelial cells, focusing on the Leukocyte Adhesion Molecule-1. LAM-1 (also called TQ1, Leu-8) is a member of a new family of cellular adhesion molecules, termed selectins, which contain a lectin-like domain at their amino terminus, followed by an epidermal growth factor-like domain and short consensus repeat units similar to those found in complement regulatory proteins. LAM-1 plays a critical role in lymphocyte trafficking by mediating binding to the high endothelial venules (HEV) of peripheral lymph nodes. In addition, LAM-1 is also likely to play a role in the regulation of leukocyte migration to sites of inflammation. LAM-1 is shed from the cell-surface following cellular activation and may therefore also regulate leukocyte migration as a circulating agent. The purpose of this study is to determine the role of LAM-1 in lymphocyte and neutrophil adhesion, how the expression of this cell-surface molecule regulates the migration of leukocytes to regions of importance, and how the structure of LAM-1 dictates its function. The functional capacity of the shed LAM-1 will also be examined to determine its potential role for modifying leukocyte migration. The ligand(s) of this adhesion receptor will also be identified and characterized. In addition to providing a clearer understanding of the molecular events that regulate leukocyte migration and adhesion, these studies may provide biological reagents with clinical utility. For example, we have engineered a soluble form of LAM-1 which blocks binding of leukocytes to endothelial cells. This reagent may prove useful for blocking the dissemination of certain lymphoid tumors or inhibiting the entry of cytotoxic T cells into transplanted organs. Also, since LAM-1 is shed by leukocytes during activation, quantification of the levels of LAM-1 in serum of patients with malignancies or inflammatory disorders may be useful for diagnosis and monitoring of disease status. Finally these studies will also provide a solid basis for understanding the mechanisms by which currently used biologic response modifying agents, such as GM-CSF and IL-2, are able to dramatically alter leukocyte migration in cancer patients undergoing cytokine therapy.
| Ma-Krupa, Wei; Jeon, Myung-Shin; Spoerl, Silvia et al. (2004) Activation of arterial wall dendritic cells and breakdown of self-tolerance in giant cell arteritis. J Exp Med 199:173-83 |
| Friedline, Randall H; Wong, Carmen P; Steeber, Douglas A et al. (2002) L-selectin is not required for T cell-mediated autoimmune diabetes. J Immunol 168:2659-66 |
