Published online before print September 19, 2005, doi: 10.1161/CIRCULATIONAHA.105.546150
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(Circulation. 2005;112:2031-2039.)
© 2005 American Heart Association, Inc.
Vascular Medicine |
Targeting Adhesion Molecules as a Potential Mechanism of Action for Intravenous Immunoglobulin
From the Immunology Research Group, Department of Physiology and Biophysics (V.G., D.K., E.L., P.K.), Faculty of Medicine (C.D.), University of Calgary, Calgary, Alberta, Canada.
Correspondence to Paul Kubes, Department of Physiology and Biophysics, Immunology Research Group, University of Calgary, Health Sciences Centre, 3330 Hospital Dr NW, Calgary, Alberta, Canada T2N 4N1. E-mail pkubes{at}ucalgary.ca
Received February 28, 2005; revision received June 12, 2005; accepted June 17, 2005.
Background— Intravenous immunoglobulin (IVIg) therapy has been shown to have therapeutic benefit in more than 50 inflammatory and immune-related diseases; however, the potential benefit of IVIg in cardiovascular disease is more limited, in part because our understanding of the mechanisms underlying the effects of IVIg in innate immunity is incomplete.
Methods and Results— In this study, a systematic assessment of the role of IVIg in leukocyte recruitment was completed with an in vitro flow-chamber system and in vivo intravital microscopy in a feline ischemia-reperfusion model system. IVIg treatment of blood resulted in a profound decrease in recruitment of either immobilized P-selectin or E-selectin due to direct effects of IVIg on the leukocyte (not substratum). Similar results were observed on endothelium treated with histamine, which induces P-selectin–dependent rolling and ß2-integrin–dependent adhesion. IVIg reduced P-selectin glycoprotein ligand-1 (PSGL-1) antibody binding to PSGL-1 on leukocytes. Use of a ß2-integrin–dependent static assay to bypass selectin-dependent recruitment revealed some inhibitory effectiveness (60%), which suggests that the majority of the effects of IVIg were due to selectin inhibition, with some inhibition of integrin function. In vivo intravital microscopy revealed a potent inhibitory effect of IVIg on P-selectin–dependent rolling and ß2-integrin–dependent adhesion that led to reduced leukocyte recruitment and vascular dysfunction in postischemic microvessels.
Conclusions— Our data demonstrate that IVIg has direct inhibitory effects on leukocyte recruitment in vitro and in vivo through inhibition of selectin and integrin function.
Key Words: endothelium • ischemia • reperfusion • leukocytes • immunoglobulin
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