Targeting adhesion molecules as a potential mechanism of action for intravenous immunoglobulin.
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.


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 beta2-integrin-dependent adhesion. IVIg reduced P-selectin glycoprotein ligand-1 (PSGL-1) antibody binding to PSGL-1 on leukocytes. Use of a beta2-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 beta2-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.
Gill
Varinder
V
Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada.
Doig
Christopher
C
Knight
Derrice
D
Love
Emma
E
Kubes
Paul
P
D000818:Animals; D018821:CD18 Antigens / Q000378:metabolism; D002415:Cats; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D019040:E-Selectin / Q000378:metabolism; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000494:pharmacology*; D036904:Leukocyte Rolling / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D015427:Reperfusion Injury / Q000503:physiopathology*; D014652:Vascular Diseases / Q000517:prevention & control
D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D016756:Immunoglobulins, Intravenous; D019007:P-Selectin