Hu23F2G, an antibody recognizing the leukocyte CD11/CD18 integrin, reduces injury in a rabbit model of transient focal cerebral ischemia.
Neutrophils are known to mediate injury in acute ischemic stroke especially during reperfusion. Migration of neutrophils into regions of ischemic injury involves binding to the endothelial cell's intercellular adhesion molecule (ICAM-1) through the leukocyte integrin, CD11/CD18. We studied the potential for neuroprotection with a humanized antibody that binds to and blocks the functions of the CD11/CD18 integrin in a rabbit model of transient focal ischemia. Fifteen New Zealand White rabbits underwent transorbital occlusion of the left middle cerebral, anterior cerebral, and internal carotid arteries using aneurysm clips for 2 h, followed by 6 h of reperfusion. Treatment with a maximally saturating dose (4 mg/kg) of a humanized CD11/CD18 monoclonal antibody (Hu23F2G, ICOS Corp., Bothell, WA) (n = 8) or placebo (n = 7) was administered 20 min after occlusion and given as a single intravenous bolus. Hemispheric ischemic neuronal damage (IND) as seen on hematoxylin- and eosin-stained sections was significantly reduced in Hu23F2G-treated animals by 57% (Hu23F2G: 15 +/- 6.9%; placebo: 35 +/- 5%; mean +/- SEM, P < 0.05, t-test). Immunohistochemical staining with neutrophil elastase confirmed the presence of neutrophils within regions of IND in control brains. Treatment with Hu23F2G resulted in marked reduction of neutrophil infiltration. (No. of neutrophils/IND area: Hu23F2G 36.1 +/- 36.7 cm-2, placebo 460.6 +/- 101.8 cm-2, P = 0.001. ) Antagonism of neutrophil migration at the level of the CD11/CD18 integrin reduces ischemic injury in experimental stroke.
Yenari
M A
MA
Department of Neurosurgery, Stanford University Medical Center, Palo Alto, California, 94304, USA.
Kunis
D
D
Sun
G H
GH
Onley
D
D
Watson
L
L
Turner
S
S
Whitaker
S
S
Steinberg
G K
GK
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001794:Blood Pressure; D001831:Body Temperature; D018845:CD11 Antigens / Q000097:blood* / Q000276:immunology; D018821:CD18 Antigens / Q000097:blood* / Q000276:immunology; D002245:Carbon Dioxide / Q000097:blood; D006801:Humans; D016023:Integrins / Q000097:blood* / Q000276:immunology; D002546:Ischemic Attack, Transient / Q000097:blood / Q000503:physiopathology* / Q000628:therapy*; D007958:Leukocyte Count; D007962:Leukocytes / Q000502:physiology*; D008297:Male; D008833:Microcirculation / Q000473:pathology / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009504:Neutrophils / Q000473:pathology / Q000502:physiology; D010100:Oxygen / Q000097:blood; D011817:Rabbits
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018845:CD11 Antigens; D018821:CD18 Antigens; D016023:Integrins; D018696:Neuroprotective Agents; D002245:Carbon Dioxide; D010100:Oxygen; C115464:rovelizumab