Anti-VLA-4 antibody reduces intimal hyperplasia in the endarterectomized carotid artery in nonhuman primates.
OBJECTIVE
Recently, very late antigen-4 (VLA-4) has been shown to mediate initial monocyte adhesion and migration to the injured artery. We hypothesized that blocking monocyte adhesion using a specific monoclonal antibody against VLA-4 may reduce intimal hyperplasia.


METHODS
Bilateral carotid endarterectomies were performed in eight adult baboons. Among them, five animals received an intravenous bolus injection of anti-VLA-4 antibody (3 mg/kg) during surgery and again after 2 weeks. Three animals underwent bilateral carotid endarterectomies and served as untreated control subjects. Specimens were harvested at 4 weeks and subjected to morphometric analysis, cell proliferation assay, and immunostaining for macrophages.


RESULTS
All of the endarterectomized arteries were patent except for one in the treated group. The number of macrophages in the intimal tissues was significantly reduced in the treated arteries compared with that in the control vessels (15.78 +/- 3.05 cells/section versus 33.50 +/- 6.13 cells/section; p < 0.001). The cell proliferation rate was significantly lower (p < 0.001) in the treated vessels (2.88% +/- 1.07%) compared with the control vessels (4.89% +/- 0.77%). The intimal area at the endarterectomized sites of carotid arteries was significantly less (p < 0.05) in the group treated with the anti-VLA-4 antibody (1.10 +/- 0.68 mm2) than in the control group (2.00 +/- 0.52 mm2).


CONCLUSIONS
These data show that blocking monocyte adhesion by use of an anti-VLA-4 antibody significantly reduces the number of intimal macrophages, intimal cell proliferation, and intimal hyperplasia in injured carotid arteries in baboons. This study supports a central role for macrophages in the development of intimal hyperplasia and may suggest a new therapeutic strategy to prevent clinical restenosis.
Lumsden
A B
AB
Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA.
Chen
C
C
Hughes
J D
JD
Kelly
A B
AB
Hanson
S R
SR
Harker
L A
LA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D002455:Cell Division; D016894:Endarterectomy, Carotid; D006965:Hyperplasia; D039041:Integrin alpha4beta1; D019012:Integrin beta1 / Q000276:immunology / Q000502:physiology*; D016023:Integrins / Q000276:immunology / Q000502:physiology*; D008264:Macrophages / Q000473:pathology; D008297:Male; D009000:Monocytes / Q000502:physiology; D010215:Papio; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D016201:Receptors, Lymphocyte Homing / Q000276:immunology / Q000502:physiology*; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis
D000911:Antibodies, Monoclonal; D039041:Integrin alpha4beta1; D019012:Integrin beta1; D016023:Integrins; D018809:Proliferating Cell Nuclear Antigen; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1