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_L-Integrin I domain cyclic peptide antagonist selectively inhibits T cell adhesion to pancreatic islet microvascular endothelium

¹Department of Pathology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana; and ²Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas

Submitted 22 June 2004 ; accepted in final form 14 August 2004

Insulitis is a hallmark feature of autoimmune diabetes that ultimately results in islet -cell destruction. We examined integrin requirements and specific inhibition of integrin structure in T cell and monocyte adhesion to pancreatic islet endothelium. Examination of cell surface integrin expression on WEHI 7.1 T cells revealed prominent expression of -, ₁-, _L-integrins, and low expression of _M-integrins; whereas WEHI 274.1 monocytes showed significant staining for ₂-, ₁-, _M-molecules and no expression of _L-molecules. Unstimulated islet endothelium showed constitutive levels of ICAM-1 counter-ligand expression with minimal VCAM-1 expression; however, TNF- stimulation increased cell surface density of both molecules. TNF- increased T cell and monocyte rolling and adhesion under hydrodynamic flow conditions. Administration of a cyclic peptide competitor for the _L-integrin I domain binding sites (cyclo1,12-PenITDGEATDSGC) blocked T cell adhesion without inhibiting monocyte adhesion. Examination of T cell rolling revealed that cLAB.L treatment increased the average rolling velocity on activated endothelium and significantly decreased the fraction of T cells rolling at 50 µm/s, suggesting that cLAB.L treatment interferes with signal activation events required for the conversion of T cell rolling to firm adhesion. These data demonstrate for the first time that cyclic peptide antagonists against _L-integrin I domain attenuate T cell recruitment to islet endothelium.

lymphocyte function-associated antigen-1; leukocyte; pancreas; diabetes

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