β7 integrins contribute to demyelinating disease of the central nervous system

A role for alpha 4 integrins in different forms of the multiple sclerosis-like disease experimental autoimmune encephalomyelitis (EAE) has been demonstrated. but the individual contributions of alpha 4 beta 1, alpha 4 beta 7, and the related alpha E beta 7 integrin have not been determined. The beta 7 integrins alpha 4 beta 7 and alpha E beta 7 play a central role in chronic inflammation, mediating the trafficking, entry, and/or adhesion of lymphocytes in the inflamed pancreas and gut, and their ligands MAdCAM-1 VCAM-1 and E-cadherin are expressed on brain endothelial cells and/or on microvessels in the inflamed central nervous system. Here, we show that an antibody directed against the beta 7 subunit greatly attenuates a non-remitting form of EAE, induced by adoptive transfer of myelin oligodendrocyte peptide (MOG(35-55))-stimulated T cells. Combinational treatment with both anti-beta 7 and alpha 4 integrin subunit antibodies led to more rapid and complete remission than that obtained with anti-alpha 4 antibody alone, potentially implicating a role for alpha E beta 7 in disease progression. Remission correlated with the down-regulation of the vascular addressins VCAM-1. MAdCAM-1. and ICAM-1 on cerebral blood vessels. Attenuated forms of disease were induced by adoptive transfer of either wild-type encephalitogenic T cells to beta 7-deficient gene knockout mice, or of beta 7(-/-)encephalitogenic T cells to wild-type recipients. The former finding indicates that beta 7(+ve) recruited cells contribute to disease progression. Thus alpha 4 beta 1, alpha 4 beta 7 and alpha E beta 7 integrins may all play a contributory role in the progression of chronic forms of demyelinating disease, and together with their ligands could represent potential targets for improved treatment of some forms of multiple sclerosis. (C) 2000 Elsevier Science B.V. All rights reserved.