Glycosylation-dependent inhibition of cutaneous lymphocyte-associated antigen expression: implications in modulating lymphocyte migration to skin

被引:59
作者
Dimitroff, CJ
Bernacki, RJ
Sackstein, R
机构
[1] Harvard Univ, Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA
[2] Harvard Univ, Brigham & Womens Hosp, Skin Dis Res Ctr, Boston, MA 02115 USA
[3] Roswell Pk Canc Inst, Grace Canc Drug Ctr, Dept Pharmacol & Therapeut, Buffalo, NY 14263 USA
[4] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA
关键词
D O I
10.1182/blood-2002-06-1736
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Constitutive E-selectin expression on dermal microvascular endothelial cells plays a critical role in mediating rolling adhesive interactions of human skin-homing T cells and in pathologic accumulation of lymphocytes in skin. The major E-selectin ligand on human skin-homing T cells is cutaneous lymphocyte-associated antigen (CLA), a specialized glycoform of P-selectin glycoprotein ligand-1 (PSGL-1) defined by monoclonal antibody HECA-452. Since HECA-452 reactivity, and not PSGL-1 polypeptide itself, confers the specificity of human T cells to enter dermal tissue, inhibition of HECA-452 expression is a potential strategy for modulating lymphocyte migration to skin. In this study, we examined the efficacy of several well-characterized metabolic inhibitors of glycosylation and of a novel fluorinated analog of N-acetylglucosamine (2-acetamido-1,3,6-tri-O-acetyl-4-deoxy-4- fluoro-D-glucopyranose [4-F-GlcNAc]) to alter HECA-452 expression on human CLA(+) T cells and prevent cell tethering and rolling on selectins under shear stress. At concentrations that did not affect PSGL-1 expression, we found that swainsonine (inhibitor of complex-type N-glycan synthesis) had no effect on HECA-452 expression or selectin ligand activity, whereas benzyl-O-N-acetylgalactosamide (BAG; inhibitor of O-glycan biosynthesis) ablated HECA-452 expression on PSGL-1 and significantly lowered selectin ligand activity. We found that 4-F-GlcNAc (putative inhibitor of poly-N-acetyllactosamine biosynthesis) was more potent than BAG at lowering HECA-452 expression and selectin binding. In addition, we show that 4-F-GlcNAc was directly incorporated into native CLA expressed on T cells, indicating direct inhibition on poly-N-acetyllactosamine elongation and selectin-binding determinants on PSGL-1 0-glycans. These observations establish a potential treatment approach for targeting pathologic lymphocyte trafficking to skin and indicate that 4-F-GlcNAc may be a promising agent for treatment of dermal tropism associated With malignancies and inflammatory disorders. (C) 2003 by The American Society of Hematology.
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页码:602 / 610
页数:9
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