Cutting edge: Natalizumab blocks adhesion but not initial contact of human T cells to the blood-brain barrier in vivo in an animal model of multiple sclerosis.
The humanized anti-alpha(4) integrin Ab Natalizumab is an effective treatment for relapsing-remitting multiple sclerosis. Natalizumab is thought to exert its therapeutic efficacy by blocking the alpha(4) integrin-mediated binding of circulating immune cells to the blood-brain barrier (BBB). As alpha(4) integrins control other immunological processes, natalizumab may, however, execute its beneficial effects elsewhere. By means of intravital microscopy we demonstrate that natalizumab specifically inhibits the firm adhesion but not the rolling or capture of human T cells on the inflamed BBB in mice with acute experimental autoimmune encephalomyelitis (EAE). The efficiency of natalizumab to block T cell adhesion to the inflamed BBB was found to be more effective in EAE than in acute systemic TNF-alpha-induced inflammation. Our data demonstrate that alpha(4) integrin-mediated adhesion of human T cells to the inflamed BBB during EAE is efficiently blocked by natalizumab and thus provide the first direct in vivo proof of concept of this therapy in multiple sclerosis.
Theodor Kocher Institute, University of Bern, Bern, Switzerland.
Caroline
C
Coisne
Wenxian
W
Mao
Britta
B
Engelhardt
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D036904:Leukocyte Rolling / Q000187:drug effects; D051379:Mice; D008856:Microscopy, Fluorescence; D009103:Multiple Sclerosis / Q000188:drug therapy; D000069442:Natalizumab; D013601:T-Lymphocytes / Q000187:drug effects*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000069442:Natalizumab