Reduction of experimental canine myocardial reperfusion injury by a monoclonal antibody (anti-Mo1, anti-CD11b) that inhibits leukocyte adhesion.
A monoclonal antibody (904) that binds to a leukocyte cell adhesion-promoting glycoprotein, (Mo1; CD11b/CD18) was administered (1 mg/kg, iv.) to open chest anesthetized dogs 45 min after the induction of regional myocardial ischemia. Ischemia was produced by occluding the left circumflex coronary artery (LCX) for 90 min and then reperfusing for 6 h. There was no difference between control and antibody treated groups with respect to arterial blood pressure, heart rate, or LCX blood flow. Administration of antibody produced no observable effect on circulating neutrophil counts, suggesting that antibody-bound neutrophils were not cleared from the circulation. The mean size of myocardial infarct expressed as percentage of the area at risk of infarction that resulted was reduced by 46% with anti-Mo1 treatment (25.8 +/- 4.7%, n = 8) compared to control (47.6 +/- 5.7%, n = 8; P less than 0.01). The area at risk of infarction was similar between groups. Circulating (serum) antibody excess was confirmed in all 8 anti-Mo1 treated dogs by immunofluorescence analysis. Analysis of ST segment elevation on the electrocardiogram as an indicator of the severity of ischemia suggests that the anti-Mo1 reduces infarct size independent of the severity of ischemia. An additional group of dogs (n = 5) was tested with a control monoclonal antibody of the same subtype (murine IgG1) and was found to produce no significant reduction in myocardial infarct size. Accumulation of neutrophils within the myocardium was significantly attenuated with 904 treatment when analyzed by histological methods. These data demonstrate that administration of anti-Mo1 monoclonal antibody after the induction of regional myocardial ischemia results in reduced myocardial reperfusion injury as measured by ultimate infarct size.
Simpson
P J
PJ
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109-0010.
Todd
R F
RF
Fantone
J C
JC
Mickelson
J K
JK
Griffin
J D
JD
Lucchesi
B R
BR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000943:Antigens, Differentiation / Q000502:physiology*; D002448:Cell Adhesion; D003326:Coronary Circulation; D003327:Coronary Disease / Q000628:therapy; D004285:Dogs; D006439:Hemodynamics; D007958:Leukocyte Count; D007962:Leukocytes / Q000166:cytology*; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy*
D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation