Sulfated L-selectin ligands as a therapeutic target in chronic inflammation

Abstract

The homing of lymphocytes to peripheral lymph nodes is initiated by an adhesive interaction between L-selectin on lymphocytes and peripheral node addressin (PNAd), a set of sialomucins displayed on high endothelial venules (HEVs) of lymph nodes. The monoclonal antibody MECA-79 reacts with the PNAd sialomucins by recognizing an N-acetylglucosamine (GlcNAc)-6-sulfated oligosaccharide, which overlaps with sialyl 6-sulfo Lewis X, the L-selectin recognition determinant. Two HEV-expressed sulfotransferases, GlcNAc6ST-1 and GlcNAc6ST-2, are essential for the expression of the MECA-79 epitope and L-selectin ligand activity on lymph-node HEVs. PNAd, as defined by MECA-79 staining, is also expressed on activated blood vessels at several sites of chronic inflammation. Recent evidence indicates that the same two sulfotransferases underlie the formation of functional PNAd at these sites. Experiments in a sheep model of asthma demonstrate that a chronic inflammatory disease can be ameliorated by targeting PNAd.