Targeting CCR2 or CD18 inhibits experimental in-stent restenosis in primates: inhibitory potential depends on type of injury and leukocytes targeted.
A central role for leukocytes in neointimal hyperplasia after arterial injury is suspected. However, the relative importance of neutrophils and monocytes in balloon or stent-induced injury are not well understood, and mechanistic targeting of leukocyte recruitment or function is crude. We determined the temporal and spatial distribution of different leukocytes after balloon and stent-induced injury in primate iliac arteries. Based on these data, we targeted neutrophil and monocyte recruitment selectively after angioplasty or stent implantation and demonstrated that monocyte-specific blockade achieved via blockade of the MCP-1 receptor CCR2, was effective at reducing neointimal hyperplasia after stenting. In contrast, combined neutrophil and monocyte blockade achieved by targeting the leukocyte beta(2)-integrin beta-subunit CD18 was required to reduce neointimal hyperplasia after balloon injury. Distinct patterns of leukocyte infiltration in balloon versus stent-injured arteries predict distinct mechanisms for antiinflammatory strategies targeting neutrophils or monocytes in primates and may assist design of effective clinical strategies for optimizing vascular interventions.
Horvath
Christopher
C
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Welt
Frederick G P
FG
Nedelman
Mark
M
Rao
Patricia
P
Rogers
Campbell
C
D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000276:immunology / Q000494:pharmacology; D019917:Blood Vessel Prosthesis Implantation; D018821:CD18 Antigens / Q000096:biosynthesis / Q000187:drug effects*; D002404:Catheterization / Q000009:adverse effects; D018450:Disease Progression; D006083:Graft Occlusion, Vascular / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D006965:Hyperplasia / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D007083:Iliac Artery / Q000473:pathology / Q000601:surgery; D007150:Immunohistochemistry; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008252:Macaca fascicularis; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D015607:Stents / Q000009:adverse effects; D017539:Tunica Intima / Q000276:immunology / Q000473:pathology / Q000601:surgery; D014654:Vascular Patency / Q000187:drug effects / Q000276:immunology
D000911:Antibodies, Monoclonal; D018821:CD18 Antigens; D054390:Receptors, CCR2; D019707:Receptors, Chemokine