Endothelial targeting and enhanced antiinflammatory effects of complement inhibitors possessing sialyl Lewis(x) moieties

Michael S. Mulligan, Roscoe L. Warner, Charles W. Rittershaus, Lawrence J. Thomas, Una S. Ryan, Kimberly E. Foreman, Larry D. Crouch, Gerd O. Till, Peter A. Ward

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60 Scopus citations

Abstract

The complement inhibitor soluble complement receptor type 1 (sCR1) and a truncated form of sCR1, sCR1[desLHR-A], have been generated with expression of the selectin-reactive oligosaccharide moiety, sialyl Lewis(x) (sLe(x)), as N-linked oligosaccharide adducts. These modified proteins, sCR1sLe(x) and sCR1[desLHR-A]sLe(x), were assessed in the L-selectin- and P-selectin- dependent rat model of lung injury following systemic activation of complement by cobra venom factor and in the L-selectin-, P-selectin-, and E- selectin-dependent model of lung injury following intrapulmonary deposition of IgG immune complexes. In the cobra venom factor model, sCR1sLe(x) and sCR1[desLHR-A]sLe(x) caused substantially greater reductions in neutrophil accumulation and in albumin extravasation in lung when compared with the non- sLe(x)-decorated forms. In this model, increased lung vascular binding of sCR1sLe(x) and sCR1[desLHR-A]sLe(x) occurred in a P-selectin-dependent manner, in contrast to the absence of any increased binding of sCR1 or sCR1[desLHR-A]. In the IgG immune complex model, sCR1[desLHR-A]sLe(x) possessed greater protective effects relative to sCR1[desLHR-A], based on albumin extravasation and neutrophil accumulation. Enhanced protective effects correlated with greater lung vascular binding of sCR1[desLHR-A]sLe(x) as compared with the non-sLe(x)-decorated form. In TNF-α-activated HUVEC, substantial in vitro binding occurred with sCR1[desLHR-A]sLe(x) (but not with sCR1[desLHR-A]). This endothelial cell binding was blocked by anti-E-selectin but not by anti-P-selectin. These data suggest that sLe(x)-decorated complement inhibitors have enhanced antiinflammatory effects and appear to have enhanced ability to localize to the activated vascular endothelium.

Original languageEnglish (US)
Pages (from-to)4952-4959
Number of pages8
JournalJournal of Immunology
Volume162
Issue number8
StatePublished - Apr 15 1999

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Mulligan, M. S., Warner, R. L., Rittershaus, C. W., Thomas, L. J., Ryan, U. S., Foreman, K. E., Crouch, L. D., Till, G. O., & Ward, P. A. (1999). Endothelial targeting and enhanced antiinflammatory effects of complement inhibitors possessing sialyl Lewis(x) moieties. Journal of Immunology, 162(8), 4952-4959.