title: Inhibition of vasospasm with lymphocyte function-associated antigen-1 monoclonal antibody in a femoral artery model in rats.
abstract: OBJECTIVE
  The authors have previously shown that a monoclonal antibody (mAb) that recognizes intercellular adhesion molecule-1 (ICAM-1), also known as CD54, when administered systemically inhibits experimental vasospasm in a rat femoral artery model, suggesting that ICAM-1 and leukocyte-endothelial adhesion play a crucial role in the molecular chain of events leading to posthemorrhagic vasospasm. In this report the authors confirm this hypothesis with mAbs directed against lymphocyte function-associated antigen-1 ([LFA-1] CD11a/CD18), the molecule on the surface of leukocytes that interacts with ICAM-1.
  
  
  METHODS
  Femoral arteries in 38 Sprague-Dawley rats were isolated and exposed to autologous blood. Twenty-nine animals were then randomized into three groups and received intraperitoneal injections of anti-LFA-1 mAb (10 rats), anti-ICAM-1 mAb (10 rats), or an isotype-matched control mAb (nine rats). Injections were administered at 3 hours and 3, 6, and 9 days after surgery. Before their deaths, six animals underwent spleen harvest, and splenocytes were used in fluorescence-activated cell sorter (FACS) analysis to verify saturation of appropriate binding sites. Animals were killed at 12 days and vessels were harvested for histological study and measurement of the luminal cross-sectional area. Nine animals were randomized as earlier, killed 24 hours after a single injection of mAb, and evaluated for periadventitial infiltration of granulocytes and macrophages. Results of FACS analysis demonstrated saturation of both LFA-1 and ICAM-1 binding sites in animals treated with the respective mAb. The mean ratios of blood-exposed to saline-exposed luminal cross-sectional areas (expressed as the percentage of lumen patency) were 90.1 +/- 5.8% (mean +/- standard error of the mean) for animals treated with the anti-LFA-1 mAb (p = 0.0218), 94.2 +/- 3.3% for animals treated with the anti-ICAM-1 mAb (p = 0.0067), and 62 +/- 7.4% for animals treated with the isotype-matched control mAb. Macrophage and granulocyte counts in the periadventitial region were 39.5 +/- 3.2/hpf for animals treated with anti-LFA-1 mAb (p = 0.001), 42 +/- 3.7/hpf for animals treated with anti-ICAM-1 mAb (p = 0.003), and 72.2 +/- 6.2/hpf for control animals.
  
  
  CONCLUSIONS
  The systemic administration of anti-LFA-1 or anti-ICAM-1 mAb initiated 3 hours after exposure to autologous blood inhibits the development of delayed chronic vasospasm at 12 days in a rat femoral artery model and leads to a significant reduction in periadventitial inflammatory cells at 24 hours. The authors conclude that blocking the migration of inflammatory cells across the endothelial surface of an artery after adventitial exposure to blood prevents the initiation of biological cascades necessary for the subsequent development of chronic vasospasm.
authors.affiliation: Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Clatterbuck
authors.forename: Eric M
authors.initials: EM
authors.lastname: Oshiro
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Hoffman
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Dietsch
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.forename: Rafael J
authors.initials: RJ
authors.lastname: Tamargo
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001798:Blood Proteins / Q000494:pharmacology; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000502:physiology*; D005434:Flow Cytometry; D006098:Granulocytes / Q000276:immunology; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013194:Staining and Labeling; D013345:Subarachnoid Hemorrhage / Q000276:immunology / Q000628:therapy; D014661:Vasoconstriction / Q000276:immunology*; D020301:Vasospasm, Intracranial / Q000276:immunology / Q000628:therapy*
chemical_list: D000911:Antibodies, Monoclonal; D001798:Blood Proteins; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1