DNA APTAMERS BLOCK L-SELECTIN FUNCTION IN-VIVO - INHIBITION OF HUMAN LYMPHOCYTE TRAFFICKING IN SCID MICE

Selectins participate in the initial events leading to leukocyte extra vasation from the blood into tissues. Thus the selectins have generate d much interest as targets for antiinflammatory agents. Therapeutic mo lecules based on the monomeric carbohydrate ligand sialyl Lewis X (SLe (x)) have low affinities and are not specific for a given selectin. Us ing SELEX (Systematic Evolution of Ligands by EXponential Enrichment) technology, we have generated aptamers specific for L-selectin that re quire divalent cations for binding and have low nanomolar affinity, In vitro, the deoxyoligonucleotides inhibit L-selectin binding to immobi lized SCex in static assays and inhibit L-selectin-mediated rolling of human lymphocytes and neutrophils on cytokine-activated endothelial c ells in flow-based assays. These aptamers also block L-selectin-depend ent lymphocyte trafficking in vivo, indicating their potential utility as therapeutics.