Blockade of CD28/B7 interaction prevents epitope spreading and clinical relapses of murine relapsing EAE

Immunization of SJL/J mice with the immunodominant epitope on myelin proteolipid protein (PLP139-151) results in a relapsing-remitting form of EAE (REAE). The acute clinical episode of disease is mediated by PLP139-151-specific CD4+ T cells, but the primary relapse is mediated predominantly by T cells specific for a secondary, non-crossreactive PLP epitope (PLP178-191) activated in response to myelin epitopes released during the acute disease episode (I.e., epitope spreading). The CD28/B7 costimulatory pathway is involved in the progression of clinical paralysis in R-EAE following the initial clinical episode. B71 was preferentially upregulated on CNS-resident and infiltrating mononuclear cells during the acute phase of EAE. There was also a selective increase in functional costimulatory activity of B7-1, relative to B7-2, in the splenic APCs from mice, undergoing chronic-relapsing EAE. The critical role of B7-1 in disease progression was highlighted by the ability of and B7-1 F(ab) fragment, but not anti-B7-2 mAb therapy, to effectively block clinical relapses, ameliorate CMS pathology and block epitope spreading when administered during clinical remission. In contrast, injection of intact anti-B7-1 mAb resulted in significant exacerbation of the incidence and severity of clinical relapses, due to its ability to provide costimulation via B7-1 expressed on activated encephalitogenic T cells. These results suggest that the maintenance of autoimmune reactivity in R-EAE depends on CD28/B7-1 -dependent costimulation of naive T cells that are responsible for epitope spreading. (Supported in part by NIH Grants NS30871 andNS34819).