LONG-TERM INHIBITION OF MURINE EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS USING CTLA-4-FC SUPPORTS A KEY ROLE FOR CD28 COSTIMULATION

T cell activation involves not only recognition of antigen presented b y the MHC, but also nonspecific interactions termed ''costimulation.'' The costimulatory molecules B7-1 and B7-2 are ligands on antigen-pres enting cells for the CD28 and CTLA-4 receptors on T cells. Previously, a fusion protein consisting of human CTLA-4 linked to human Fc was sh own to bind B7-1 and B7-2 with high avidity and to prevent specific T cell activation. Here we investigated the effects of a recombinant fus ion protein consisting of the extracellular domain of human CTLA-4 bou nd to mouse IgG2a Fc (CTLA-4-Fc) upon experimental autoimmune encephal omyelitis, a T cell-mediated disease that serves as a model for multip le sclerosis. CTLA-4-Fc prevented experimental autoimmune encephalomye litis in 26 of 28 CTLA-4-Fc-treated mice (median maximum score 0), whe reas 28 of 30 mice treated with control mouse IgG2a developed disease (median maximum score 2.75). Less inflammation and virtually no demyel ination or axonal loss occurred in CTLA-4-Fc-treated compared with con trol-treated mice, Activated splenocytes from CTLA-4-Fc-treated mice w ere able to transfer disease adoptively to naive recipients. These res ults indicate a key role for the B7/CD28 system in the development of actively induced murine experimental autoimmune encephalomyelitis, sug gesting an area of investigation with therapeutic potential for multip le sclerosis.