Successful treatment of paralytic relapses in adoptive experimental autoimmune encephalomyelitis via neuroantigen-specific tolerance.

We have previously demonstrated that Ag-specific tolerance induced by the i.v. administration of splenocytes coupled with neuroantigens, such as mouse spinal cord homogenate, myelin basic protein (MBP), and proteolipid protein, and their encephalitogenic peptides, results in dramatic inhibition of clinical and histologic signs of both actively induced and adoptively transferred relapsing experimental autoimmune encephalomyelitis (R-EAE). We report here that the administration of splenocytes coupled with mouse spinal cord homogenate (i.e., a mixture of neuroantigens), after the first paralytic episode of adoptive R-EAE triggered by MBP-specific T cells but before the appearance of the first relapse, effectively reduced the onset and severity of all subsequent relapses, as determined by both clinical and pathologic criteria. In contrast, the i.v. administration of splenocytes coupled with MBP (i.e., the specificity of the initiating T cell response), under similar conditions, effectively inhibited the initial clinical relapse, but subsequent relapses occurred with the same incidence rate and severity as those in control animals. Collectively, these results demonstrate that neuroantigen-specific tolerance is effective at specifically down-regulating an ongoing autoimmune response. This may have potential clinical applicability for treatment of autoimmune diseases. The results also support the hypothesis that the neuroantigen specificity of later relapses of R-EAE may be due to effector T cells with specificities different from those that triggered the initial clinical episode. Thus, potential therapy for the advanced stages of R-EAE, and perhaps other autoimmune diseases, may have to be directed not simply against the effector cells initiating the disease but also against effector cells with differing specificities recruited as a result of tissue damage occurring in the initial acute disease.