Article

Sustained limitation of myocardial reperfusion injury by a monoclonal antibody that alters leukocyte function.

Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109.
Circulation (Impact Factor: 15.2). 02/1990; 81(1):226-37. DOI: 10.1161/01.CIR.81.1.226
Source: PubMed

ABSTRACT Pentobarbital anesthetized dogs were subjected to 90 minutes of left circumflex coronary artery (LCCA) occlusion followed by 72 hours of reperfusion. Control or anti-Mo1 (904) F(ab')2 fragments of monoclonal antibodies were administered intravenously at a dose of 1 mg/kg beginning 45 minutes after occlusion and at a dose of 0.5 mg/kg at 12, 24, 36, and 48 hours after reperfusion. Myocardial infarct size expressed as a percentage of the area at risk (IN/AR) measured postmortem after 72 hours of reperfusion was significantly reduced by 904 F(ab')2 (21.6 +/- 2.8%, n = 8) compared with control F(ab')2 (37.4 +/- 5.8%, n = 8; p less than 0.025). There were no significant differences between groups in heart rate, mean arterial blood pressure, rate-pressure product, or LCCA blood flow that could account for a reduced infarct size. Regional myocardial blood flow (RMBF) was determined with 15-microns radiolabeled microspheres. Transmural blood flows (ml/min/g) within the region of myocardium at risk were not statistically different between treatment groups. Infarct size in both groups was related to regional myocardial blood flow, and the relation was shifted downward in the group treated with the anti-Mo1 F(ab')2 antibody (analysis of covariance, p = 0.01). Thus, anti-Mo1 F(ab')2 produces a sustained limitation of myocardial infarct size compared with controls under similar hemodynamic conditions and a similar degree of myocardial ischemia as determined by RMBF. These data suggest that inhibition of neutrophil adhesive interactions (as suggested by the inhibitory effect of anti-Mo1 on canine neutrophil aggregation) may be an effective mechanism for protection against myocardial injury secondary to myocardial ischemia and reperfusion.

0 Bookmarks
 · 
56 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Immunotherapy represents an active area of biomedical research to treat cancer, autoimmune diseases, and neurodegenerative disorders. In stroke, recanalization therapy is effective in reducing brain tissue damage after acute ischemic stroke. However, the narrow time window restricts its application for the majority of stroke patients. There is an urgent need to develop adjuvant therapies such as immunotherapy, stem cell replacement, and neuroprotective drugs. A number of molecules have been targeted for immunotherapy in stroke management, including myelin-associated proteins and their receptors, N-methyl-d-aspartic acid receptors, cytokines, and cell adhesion molecules. Both active vaccination and passive antibodies were tested in animal models of acute ischemic stroke. However, the mechanisms underlying the efficacy of immunotherapy are different for each target protein. Blocking myelin-associated proteins may enhance neuroplasticity, whereas blocking adhesion molecules may yield neuroprotection by suppressing the immune response after stroke. Although results from animal studies are encouraging, clinical trials using therapeutic antibodies failed to improve stroke outcome due to severe side effects. It remains a challenge to generate specific therapeutic antibodies with minimal side effects on other organs and systems.
    Translational stroke research. 01/2013; 4:477-483.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The author was privileged to be an early contributor to the concept that cell adhesion molecules, the leukocyte (β2) integrins, play a pivotal role in the acute inflammatory process. For the author, this began with the development of a monoclonal antibody (anti-Mo1) that identified a differentiation antigen on the surface of human myeloid cells (including neutrophils, monocytes, and natural killer (NK) cells). Serendipitously, it was discovered that the Mo1 antigen was the heterodimeric glycoprotein (gp155,95) absent from the surface of neutrophils isolated from patients with adhesion defects in vitro and a syndrome characterized by chronic, life-threatening infections in vivo (a syndrome now termed leukocyte adhesion deficiency, type 1) (LAD-1). Collaborative efforts with other investigators (including members of the ACCA) revealed that patients with LAD-1 exhibited genetic mutations on chromosome 21 resulting in absent or diminished expression of a class of 4 surface adhesion molecules (now termed CD11a/CD18, CD11b/CD18, CD11c/CD18, and CD11d/CD18) known as the leukocyte or β2 family of integrins. Knowledge of the role of the β2 integrins in the acute inflammatory response led to the development of effective gene therapy strategies to treat LAD-1 in preclinical animal models and to the comprehensive testing of anti-integrin antibodies as anti-inflammatory agents to prevent organ damage as a complication of acute inflammation. This retrospective provides one illustration of the potential of bench-to-bedside research to generate new knowledge of clinical significance.
    Transactions of the American Clinical and Climatological Association 01/2010; 122:138-49.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Submucosal injection of endothelin (ET) -1 induces gastric ulcer. We investigated the roles of neutrophils and adhesion molecules (intercellular adhesion molecule (ICAM)-1 and CD18) in the development of ET-1-induced ulcers in rats. Ulcers were induced by submucosal injection of ET-1. Rats were injected with anti-neutrophil serum or F(ab")2 fragments of irrelevant mouse IgG2a (control), anti-ICAM-1 antibody, or anti-CD18 antibody. Ulcer tissues were subjected to measurement of myeloperoxidase (MPO) activity, ulcer size, and immunohistochemical study. Within 3 hr, arterial vasoconstriction and vascular congestion were observed at sites of ET-1 injection. By 6 hr, vascular congestion had disappeared, and ICAM-1 expression had markedly increased in venules in deep portions of the mucosa and submucosa, accompanied by an increase in the number of CD18-positive neutrophils. By 48 hr, ulcers that extended into the submucosa had developed. In controls, MPO activity gradually increased and was maximal by 6 hr. Neutrophil depletion, and immunoneutralizing of ICAM-1 and CD18 inhibited the increase in MPO activity, and decreased ulcer sizes measured at 48 hr. In conclusion, ET-1 causes ischemia–reperfusion injury, and neutrophil accumulation after reperfusion mediated by the ICAM-1-CD18 pathway may be important in the development of ET-1-induced gastric ulcer.
    Digestive Diseases and Sciences 04/2000; 45(5):880-888. · 2.26 Impact Factor

Full-text (2 Sources)

View
38 Downloads
Available from
May 21, 2014