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Sialyl Lewisx (sLex) and an sLex
Mimetic, CGP69669A, Disrupt E-Selectin-Dependent Leukocyte Rolling In
Vivo
Keith E. Norman,
Gary P. Anderson,
Hartmut C. Kolb,
Klaus Ley, and
Beat Ernst
From the Departments of Transplantation and Respiratory Diseases,
Novartis AG, Basle, Switzerland; and the Department of Biomedical
Engineering, University of Virginia Health Sciences Center,
Charlottesville, VA
Leukocyte rolling is the earliest observable event in their
recruitment from the circulation to inflamed tissue. This rolling is
mediated largely by interaction between the selectin family of adhesion
molecules and their glycosylated ligands. Although the nature of these
ligands and their interaction with the selectins is not fully
understood, it is accepted that expression of fucosylated sialylated
glycans such as sialyl Lewisx (sLex) is
required for function. Despite findings that sLex inhibits
binding of leukocytes to E-selectin in vitro, and has beneficial
effects in inflammatory disease models, inhibition of
E-selectin-dependent leukocyte rolling in vivo has not been described.
Functional overlap between the selectins has been noted and reduction
of rolling by E-selectin antibodies only occurs if P-selectin is absent
or blocked. We demonstrate that leukocyte rolling velocity in tumor
necrosis factor alpha (TNF )-stimulated mouse cremaster is increased
following treatment with either sLex or the
sLex-mimetic CGP69669A and that rolling is dramatically
reduced if CGP69669A is applied in the presence of anti-P-selectin
antibody. These effects are characteristic of E-selectin antagonism. In contrast, surgically stimulated (L- or P-selectin-dependent) rolling is unaffected by either sLex or CGP69669A. Our data
demonstrate that CGP69669A is an effective and selective antagonist of
E-selectin in vivo.
Blood, Vol. 91 No. 2 (January 15), 1998:
pp. 475-483
© 1998 by The American Society of Hematology.
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