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Alpha(4)beta(7)/alpha(4)beta(1) dual integrin antagonists block alpha(4)beta(7)-dependent adhesion under shear flow.
- Source :
-
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2002 Jul; Vol. 302 (1), pp. 153-62. - Publication Year :
- 2002
-
Abstract
- The alpha(4) integrin, alpha(4)beta(7), plays an important role in recruiting circulating lymphocytes to the gastrointestinal tract, where its ligand mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is preferentially expressed on high endothelial venules (HEVs). Dual antagonists of alpha(4)beta(1) and alpha(4)beta(7), N-(2,6-dichlorobenzoyl)-(L)-4-(2',6'-bis-methoxyphenyl)phenylalanine (TR14035) and N-(N-[(3,5-dichlorobenzene)sulfonyl]-2-(R)-methylpropyl)-(D)-phenylalanine (compound 1), were tested for their ability to block the binding of alpha(4)beta(7)-expressing cells to soluble ligand in suspension and under in vitro and in vivo shear flow. Compound 1 and TR14035 blocked the binding of human alpha(4)beta(7) to an (125)I-MAdCAM-Ig fusion protein with IC(50) values of 2.93 and 0.75 nM, respectively. Both compounds inhibited binding of soluble ligands to alpha(4)beta(1) or alpha(4)beta(7) on cells of human or rodent origin with similar potency. Under shear flow in vitro, TR14035 and compound 1 blocked binding of human alpha(4)beta(7)-expressing RPMI-8866 cells or murine mesenteric lymph node lymphocytes to MAdCAM-Ig with IC(50) values of 0.1 and 1 microM, respectively. Intravital microscopy was used to quantitate alpha(4)-dependent adhesion of fluorescent murine lymphocytes in Peyer's patch HEVs. When cells were prestimulated with 2 mM Mn(2+) to activate alpha(4)beta(7) binding to ligand, anti-alpha(4) monoclonal antibody (mAb) [10 mg/kg (mpk) i.v.] blocked adhesion by 95%, and anti-beta(1) mAb did not block adhesion, demonstrating that this interaction was dependent on alpha(4)beta(7). TR14035 blocked adhesion to HEVs [ED(50) of 0.01-0.1 mpk i.v.], and compound 1 blocked adhesion by 47% at 10 mpk i.v. Thus, alpha(4)beta(7)/alpha(4)beta(1) antagonists blocked alpha(4)beta(7)-dependent adhesion of lymphocytes to HEVs under both in vitro and in vivo shear flow.
- Subjects :
- Animals
Antibodies, Blocking pharmacology
Antibodies, Monoclonal pharmacology
Antineoplastic Combined Chemotherapy Protocols immunology
Cell Adhesion drug effects
Cell Adhesion Molecules
Cyclophosphamide immunology
Doxorubicin immunology
Endothelium, Vascular cytology
Endothelium, Vascular drug effects
Etoposide immunology
Female
Flow Cytometry
Humans
Immunoglobulin G isolation & purification
Immunoglobulin G pharmacology
Immunoglobulins
Integrin alpha4beta1
Ligands
Lymphocytes drug effects
Methotrexate immunology
Mice
Mice, Inbred BALB C
Mucoproteins antagonists & inhibitors
Peyer's Patches cytology
Peyer's Patches drug effects
Phenylalanine analogs & derivatives
Recombinant Fusion Proteins pharmacology
Rheology
Integrins antagonists & inhibitors
Phenylalanine pharmacology
Receptors, Lymphocyte Homing antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0022-3565
- Volume :
- 302
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 12065712
- Full Text :
- https://doi.org/10.1124/jpet.302.1.153