(Journal Article): {alpha}L integrin I domain cyclic peptide antagonist selectively inhibits T cell adhesion to pancreatic islet microvascular endothelium
 
Huang M, Matthews K, Siahaan TJ, Kevil CG (Department of Pathology, LSU Health Sciences Center, Shreveport, Louisiana, USA, ckevil@lsuhsc.edu )
 
IN: Am J Physiol Gastrointest Liver Physiol 2004; Epub(19)
Impact Factor(s) of Am J Physiol Gastrointest Liver Physiol: 3.479 (2004), 3.421 (2003), 3.66 (2001)

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ABSTRACT: Insulitis is a hallmark feature of autoimmune diabetes that ultimately results in islet beta 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 beta2, beta1, alphaL, and low expression of alphaM integrins; while WEHI 274.1 monocytes showed significant staining for beta2, beta1, alphaM and no expression of alphaL molecules. Unstimulated islet endothelium showed constitutive levels of ICAM-1 counter ligand expression with minimal VCAM-1 expression; however, TNF-alpha stimulation increased cell surface density of both molecules. TNF-alpha increased T cell and monocyte rolling and adhesion under hydrodynamic flow conditions. Administration of a cyclic peptide competitor for the alphaL I domain binding sites (cLAB.L, 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 micro m/sec 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 alphaL I domain attenuate T cell recruitment to islet endothelium.

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