Published Online
on September 19, 2005

A more recent version of this article appeared on September 27, 2005

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Submitted on February 28, 2005
Revised on June 12, 2005
Accepted on June 17, 2005

Targeting Adhesion Molecules as a Potential Mechanism of Action for Intravenous Immunoglobulin

Varinder Gill MSc, Christopher Doig MSc, MD, Derrice Knight , Emma Love , and Paul Kubes PhD^*

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.

^* To whom correspondence should be addressed. E-mail: pkubes{at}ucalgary.ca.

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 ₂-integrin-dependent adhesion. IVIg reduced P-selectin glycoprotein ligand-1 (PSGL-1) antibody binding to PSGL-1 on leukocytes. Use of a ₂-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 ₂-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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