beta 7 integrins contribute to demyelinating disease of the central nervous system

A role for alpha 4 integrins in different forms of the multiple sclerosis-l ike disease experimental autoimmune encephalomyelitis (EAE) has been demons trated. 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 chron ic inflammation, mediating the trafficking, entry, and/or adhesion of lymph ocytes 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 microvess els 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 (MO G(35-55))-stimulated T cells. Combinational treatment with both anti-beta 7 and alpha 4 integrin subunit antibodies led to more rapid and complete rem ission than that obtained with anti-alpha 4 antibody alone, potentially imp licating a role for alpha E beta 7 in disease progression. Remission correl ated with the down-regulation of the vascular addressins VCAM-1. MAdCAM-1. and ICAM-1 on cerebral blood vessels. Attenuated forms of disease were indu ced by adoptive transfer of either wild-type encephalitogenic T cells to be ta 7-deficient gene knockout mice, or of beta 7(-/-)encephalitogenic T cell s to wild-type recipients. The former finding indicates that beta 7(+ve) re cruited 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 wit h their ligands could represent potential targets for improved treatment of some forms of multiple sclerosis. (C) 2000 Elsevier Science B.V. All right s reserved.