IVIg therapy in brain inflammation: etiology-dependent differential effects on leucocyte recruitment.
Several studies have reported beneficial effects of intravenous immunoglobulin (IVIg) in diseases of the neuroaxis. However, IVIg effects on leucocyte recruitment, a hallmark feature of autoimmunity and acute inflammation, remain largely unexplored. Using intravital microscopy, we studied the effects of IVIg on leucocyte recruitment in experimental autoimmune encephalomyelitis, a model of multiple sclerosis. In IVIg-treated mice, a significant decrease in recruitment (rolling and adhesion) was observed prior to and following disease onset, and this was concomitant with improved clinical score. Since much of the recruitment is dependent upon alpha4-integrin (ligand for VCAM-1) we used an in vitro flow chamber system and demonstrated a 60% decrease in alpha4-integrin-dependent leucocyte adhesion to immobilized VCAM-1. Finally, we used leucocytes from multiple sclerosis patients and demonstrated that IVIg treatment decreased recruitment by 60% on human endothelium. However, when we visualized the role of IVIg in a second model of brain inflammation, cerebral ischaemia-reperfusion, IVIg actually promoted the formation of platelet-leucocyte aggregates in post-ischaemic cerebral vessels. In conclusion, we report a new mechanism of action of IVIg through interference of alpha4-integrin-dependent leucocyte recruitment in both an animal model and human multiple sclerosis. We also report that IVIg will not be beneficial in all types of pro-adhesive states and may in fact be detrimental in a situation such as stroke.
Lapointe
Benoît M
BM
Immunology Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, AB, Canada.
Herx
Leonie M
LM
Gill
Varinder
V
Metz
Luanne M
LM
Kubes
Paul
P
D000328:Adult; D000818:Animals; D002448:Cell Adhesion / Q000276:immunology; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology / Q000628:therapy*; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology; D004730:Endothelium, Vascular / Q000276:immunology; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000276:immunology / Q000627:therapeutic use* / Q000633:toxicity; D039441:Integrin alpha4 / Q000502:physiology; D007962:Leukocytes / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000276:immunology; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000209:etiology / Q000276:immunology / Q000628:therapy*; D015427:Reperfusion Injury / Q000276:immunology; D020521:Stroke / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D016756:Immunoglobulins, Intravenous; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4