A mAb to the beta2-leukocyte integrin Mac-1 (CD11b/CD18) reduces intimal thickening after angioplasty or stent implantation in rabbits.
Leukocytes are recruited early and abundantly to experimentally injured vessels, in direct proportion to cell proliferation and intimal growth. Activated circulating leukocytes and Mac-1 (CD11b/CD18, alphaMbeta2) expression are markers of restenosis risk in patients undergoing angioplasty. As angioplastied vessels lack endothelium but have extensive fibrin(ogen) and platelet deposition, we hypothesized that Mac-1-dependent adhesion to fibrin(ogen) is an important determinant of leukocyte recruitment and function, which may in turn promote intimal growth. To study this hypothesis we administered M1/70, an anti-CD11b blocking mAb, to rabbits (1 mg/kg i.v.) immediately before, and every 48 hr for 3, 6, or 14 days after, iliac artery balloon denudation or deeper stent-induced injury. M1/70, which bound to isolated rabbit monocytes and dose-dependently inhibited Mac-1-mediated fibrinogen binding in vitro, reduced leukocyte recruitment more than 2-fold 3, 6, and 14 days after injury. Neointimal growth 14 days after injury was markedly attenuated by treatment with M1/70 (intimal area after balloon injury, 0.12 +/- 0.09 mm2, compared with 0.32 +/- 0.08 mm2 in vehicle-treated controls, P < 0.01, and 0.38 +/- 0.08 mm2 in IgG-treated controls, P < 0.005; intimal area after stent injury, 0. 56 +/- 0.16 mm2, compared with 0.84 +/- 0.13 mm2 in vehicle-treated controls, P < 0.05, and 0.90 +/- 0.15 mm2 in IgG-treated controls, P < 0.02). Mac-1 blockade reduces experimental neointimal thickening, suggesting that leukocyte recruitment to and infiltration of injured arteries may be a valid target for preventing intimal hyperplasia.
Rogers
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Department of Medicine, Cardiac Catheterization Laboratory and Coronary Care Unit, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. cdrogers@bics.bwh.harvard.edu
Edelman
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Simon
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D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D018821:CD18 Antigens / Q000276:immunology / Q000502:physiology*; D002448:Cell Adhesion; D002455:Cell Division; D002465:Cell Movement; D006801:Humans; D006965:Hyperplasia; D007083:Iliac Artery / Q000276:immunology / Q000293:injuries* / Q000473:pathology; D007249:Inflammation / Q000473:pathology / Q000517:prevention & control; D007962:Leukocytes / Q000276:immunology / Q000473:pathology / Q000502:physiology; D008297:Male; D011817:Rabbits; D015607:Stents / Q000009:adverse effects*
D000911:Antibodies, Monoclonal; D018821:CD18 Antigens