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Richard E. Clatterbuck, Philippe Gailloud, Lynn Ogata, Abeyu Gebremariam, Gregory N. Dietsch, Kieran J. Murphy, and Rafael J. Tamargo

Object. Leukocyte—endothelial cell interactions occurring in the first hours after subarachnoid hemorrhage (SAH) initiate changes in the endothelium and vessel wall that lead to an influx of leukocytes and the development of chronic vasospasm days later. Upregulation of intercellular adhesion molecule—1 (ICAM-1), also called CD54, appears to be a crucial step in this process. There is increasing experimental evidence that blocking the interaction between ICAM-1, which is expressed on endothelium, and integrins such as lymphocyte function—associated antigen—1 (CD11a/CD18) and macrophage antigen—1 (complement receptor 3, CD11b/CD18), which are expressed on the surface of leukocytes, prevents not only inflammation of vessel walls but also chronic vasospasm. The authors extend their previous work with monoclonal antibody (mAb) blockade of leukocyte migration to a nonhuman primate model of chronic, posthemorrhagic cerebral vasospasm.

Methods. Before surgery was performed, six young adult male cynomolgus monkeys underwent baseline selective biplane common carotid and vertebrobasilar artery cerebral angiography via a transfemoral route. On Day 0, a right frontosphenotemporal craniectomy was performed with arachnoid microdissection and placement of 2 to 3 ml of clotted autologous blood in the ipsilateral basal cisterns. The animals were given daily intravenous infusions of 2 mg/kg of either a humanized anti-CD11/CD18 or a placebo mAb beginning 30 to 60 minutes postoperatively. The monkeys were killed on Day 7 after a repeated selective cerebral angiogram was obtained. The area of contrast-containing vessels observed in each hemisphere on anteroposterior angiographic views was calculated for the angiograms obtained on Day 7 and expressed as a percentage of the area on baseline angiograms (percent control areal fraction). Review of flow cytometry and enzyme immunoassay data confirmed the presence of the anti-CD11/CD18 antibody in the serum and bound to leukocytes in the peripheral blood of treated animals. Comparisons of the groups revealed 53 ± 4.8% control vascular areal fraction in the placebo group (two animals) and 95.8 ± 9.4% in the anti-CD11/CD18—treated group (three animals), a statistically significant difference (p = 0.043, t-test).

Conclusions. These results show that blockade of leukocyte migration into the subarachnoid space by an anti-CD11/CD18 mAb is effective in preventing experimental cerebral vasospasm in nonhuman primates, despite the unaltered presence of hemoglobin in the subarachnoid space. These experimental data support the hypothesis that inflammation plays a role in cerebral vasospasm after SAH.

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Richard E. Clatterbuck, Eric M. Oshiro, Patricia A. Hoffman, Gregory N. Dietsch, Drew M. Pardoll, and Rafael J. Tamargo

Object. 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.