Prevention of a chronic progressive form of experimental autoimmune encephalomyelitis by an antibody against mucosal addressin cell adhesion molecule-1, given early in the course of disease progression

A role for alpha4 and beta7 integrins in mediating leucocyte entry into the central nervous system in the multiple sclerosis (MS)-like disease experim ental autoimmune encephalomyelitis (EAE) has been demonstrated. However, th e individual contributions of their respective ligands mucosal addressin ce ll adhesion molecule-1 (MAdCAM-1), vascular cell adhesion molecule-1 (VCAM- 1) and E-cadherin expressed on the blood-brain barrier has not been determi ned. In the present paper, it is shown that an antibody directed against MA dCAM-1, the preferential ligand for alpha4 beta7, effectively prevented the development of a progressive, non-remitting, form of EAE, actively induced by injection of myelin oligodendrocyte glycoprotein peptide (MOG(35-55)) a utoantigen. Combinational treatment with both anti-MAdCAM-1, VCAM-1, and in tercellular adhesion molecule-1 (ICAM-1) (ligand for integrin lymphocyte fu nction-associated antigen (LFA)-1) mAbs led to more rapid remission than th at obtained with anti-MAdCAM-1 antibody alone. However, neither MAdCAM-1 mo notherapy, nor combinational antibody blockade was preventative when admini stered late in the course of disease progression. In conclusion, MAdCAM-1 p lays a major contributory role in the progression of chronic EAE and is a p otential therapeutic target for the treatment of MS. Critically, antivascul ar addressin therapy must be given early in the course of disease prior to the establishment of irreversible damage if it is to be effective, as a sin gle treatment modality.