BLOCKADE OF CD28 B7-1 INTERACTION PREVENTS EPITOPE SPREADING AND CLINICAL RELAPSES OF MURINE EAE/

Relapsing experimental autoimmune encephalomyelitis (R-EAE) induced wi th the immunodominant epitope from proteolipid protein, PLP(139-151), is characterized by the development of recurrent relapses with recruit ment of T cells reactive to additional myelin peptides, including PLP( 178-191) (epitope spreading). In this study, we have determined that t he CD28/B7 costimulatory pathway is involved in this process. We found preferential up-regulation of B7-1 during the course of R-EAE and a s elective increase in its functional costimulatory activity, relative t o B7-2. Anti B7-1 F(ab) fragment therapy, but not anti B7-2 MAb therap y, blocked clinical relapses, ameliorated CNS pathology, and blocked e pitope spreading. These results suggest that the maintenance of autoim mune reactivity in EAE depends on CD28/B7-1-dependent costimulation of newly recruited T cells responsible for epitope spreading. These stud ies have important implications for the role of epitope spreading in d isease progression and the clinical application of costimulatory antag onists in autoimmune diseases.