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 extravasation from the blood into tissues. Thus the selectins have generated much interest as targets for antiinflammatory agents. Therapeutic molecules based on the monomeric carbohydrate ligand sialyl Lewis X (SLe(X)) have low affini...

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Bibliographic Details
Published in:The Journal of clinical investigation 1996-12, Vol.98 (12), p.2688-2692
Main Authors: Hicke, B J, Watson, S R, Koenig, A, Lynott, C K, Bargatze, R F, Chang, Y F, Ringquist, S, Moon-McDermott, L, Jennings, S, Fitzwater, T, Han, H L, Varki, N, Albinana, I, Willis, M C, Varki, A, Parma, D
Format: Article
Language:English
Subjects:
Animals
Binding Sites
Calcium - pharmacology
Cell Adhesion - drug effects
Cloning, Molecular
Deoxyribonucleotides - chemistry
Deoxyribonucleotides - pharmacology
DNA-Binding Proteins - metabolism
Flow Cytometry
L-Selectin - metabolism
Lewis X Antigen
Ligands
Lymphocytes - metabolism
Mice
Mice, SCID
Protein Binding - drug effects
Spectrometry, Fluorescence
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Summary:Selectins participate in the initial events leading to leukocyte extravasation from the blood into tissues. Thus the selectins have generated much interest as targets for antiinflammatory agents. Therapeutic molecules based on the monomeric carbohydrate ligand sialyl Lewis X (SLe(X)) have low affinities and are not specific for a given selectin. Using SELEX (Systematic Evolution of Ligands by EXponential Enrichment) technology, we have generated aptamers specific for L-selectin that require divalent cations for binding and have low nanomolar affinity. In vitro, the deoxyoligonucleotides inhibit L-selectin binding to immobilized SLe(X) in static assays and inhibit L-selectin-mediated rolling of human lymphocytes and neutrophils on cytokine-activated endothelial cells in flow-based assays. These aptamers also block L-selectin-dependent lymphocyte trafficking in vivo, indicating their potential utility as therapeutics.
ISSN:0021-9738
DOI:10.1172/jci119092