Alpha L-integrin I domain cyclic peptide antagonist selectively inhibits T cell adhesion to pancreatic islet microvascular endothelium.
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 beta-, beta(1)-, alpha(L)-integrins, and low expression of alpha(M)-integrins; whereas WEHI 274.1 monocytes showed significant staining for beta(2)-, beta(1)-, alpha(M)-molecules and no expression of alpha(L)-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 alpha(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 < or =50 microm/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 alpha(L)-integrin I domain attenuate T cell recruitment to islet endothelium.
Dept. of Pathology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71130, USA.
Meng
M
Huang
Kametra
K
Matthews
Teruna J
TJ
Siahaan
Christopher G
CG
Kevil
D000818:Animals; D002448:Cell Adhesion; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology*; D039423:Integrin alpha1 / Q000096:biosynthesis* / Q000494:pharmacology*; D016023:Integrins / Q000096:biosynthesis / Q000502:physiology; D007515:Islets of Langerhans / Q000502:physiology*; D051379:Mice; D009000:Monocytes / Q000502:physiology; D010446:Peptide Fragments; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology*
D039423:Integrin alpha1; D016023:Integrins; D010446:Peptide Fragments