The movement of lymphocytes from the blood into secondary lymphoid organs, such as lymph nodes, and back to the blood again is known as lymphocyte recirculation. This process is an essential component of immune surveillance. A primary step in the """"""""homing"""""""" of lymphocytes into a lymphoid organ is their highly specific adhesion to the specialized endothelial lining of postcapillary venules known as high endothelial venules or HEV. The initial interaction of lymphocytes with lymph node HEV is mediated by a lectin-like receptor on the lymphocyte known as L- selectin, which recognizes a discrete set of carbohydrate-based ligands on the endothelium. Two of the ligands that are associated with HEV are GlyCAM-1 and CD34. A major aim of the present application is the identification of additional ligands and a determination of how they function in coordination with GlyCAM-1 and CD34 in the complex homing process. The initial interaction of lymphocytes with HEV does not lead to firm adherence unless a second adhesive molecule is activated. The activation of this molecule, known as LFA-1, appears to depend on signals that are transmitted through L-selectin. The interaction of L-selectin with GlyCAM-1 may trigger this signaling.
An aim of this proposal is to understand the mechanism of this signaling. The ligands for L-selectin all contain complex sugar structures which are essential to their binding by this receptor. One of the distinctive features of these sugars is their modification by sulfate. Structural analysis has guided the synthesis of relatively simple sulfated sugars, which are believed to mimic the essential features of the real biological ligands. The proposal will evaluate these synthetic compounds to determine how well they bind to L-selectin and whether they are capable of blocking its adhesive function on cells. The proposed research will also investigate the process by which the complex sugars are synthesized. In particular, the enzyme that is responsible for adding sulfate to the sugars will be identified and characterized. From these studies, a fuller picture will emerge of how lymphocytes migrate into lymph nodes during the normal process of lymphocyte recirculation. Since similar adhesive mechanisms appear to operate in the targeting of leukocytes to inflammatory sites, this knowledge may assist in the development of therapeutics to treat inflammatory diseases.
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