The effects of neuroantigen-specific tolerance on the induction and effector stages of relapsing experimental autoimmune encephalomyelitis (R-EAE) were examined. The incidence of clinical and histologic signs of active MSCH-induced R-EAE, and accompanying neuroantigen-specific DTH responses, were dramatically reduced in SJL/J mice tolerized via the i.v. injection of syngeneic splenocytes coupled with MSCH, PLP, or encephalitogenic PLP peptides 7-14 days before priming. MBP-specific tolerance was not effective in preventing active R-EAE. In contrast to MSCH-induced active R-EAE, treatment of recipient mice with splenocytes coupled with MBP and the encephalitogenic MBP 84-104 peptide, but not with PLP, suppressed of clinical signs of adoptive R-EAE mediated by MBP-specific effector T cells in a dose-dependent manner. Neuroantigen-coupled splenocytes were also efficient in treating established disease as tolerization of SJL/J mice after the first incidence of clinical disease significantly reduced the incidence and severity of subsequent paralytic relapses. Antigen-specific tolerance thus provides a powerful approach for the prevention and/or treatment of autoimmune disease.