Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale.
The symptoms, severity, and course of multiple sclerosis (MS) vary among patients, leading to complex treatment issues. In recent years, research has focused on specific adhesion molecules that participate in the activation and function of lymphocytes, especially the migration of these cells to sites of inflammation. In particular, the integrin, very late activation antigen (VLA)-4, has been implicated in mediating adhesion and migration of immune cells through interaction with its ligand, vascular cell adhesion molecule (VCAM)-1. VLA-4 is comprised of alpha4/beta1 and is critical in mediating Th-1 cell migration in the animal model of MS, experimental autoimmune encephalomyelitis, and has been the target of several recent clinical trials in MS. The humanized monoclonal antibody to alpha4 integrin, natalizumab (Tysabri, Biogen Idec/Elan), was recently approved in the United States for the treatment of relapsing MS. The authors discuss the mechanisms by which alpha4 integrins alter lymphocyte function as a rationale for anti-alpha4 integrin use in MS.
Rice
George P A
GP
Department of Clinical Neurologic Sciences, University of Western Ontario, London Health Sciences Centre, University Campus, 339 Windermere Road, London, Ontario, Canada N6A 5A5. grice@uwo.ca
Hartung
Hans-Peter
HP
Calabresi
Peter A
PA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D039441:Integrin alpha4 / Q000187:drug effects* / Q000276:immunology; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors / Q000276:immunology; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D000069442:Natalizumab; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D039041:Integrin alpha4beta1; D000069442:Natalizumab; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4