EAE is an autoimmune disease of the central nervous system (CNS) that can be actively induced in animals by a single intradermal injection of whole CNS myelin or isolated myelin basic protein (MBP) homogenized in complete Freund?s adjuvant (CFA). Immunized animals develop hindlimb paralysis in 10-14 days mediated by autoaggressive MBP-specific T lymphocytes and then spontaneously recover by day 18 after injection. Also, the acute stage of the disease actively induced with whole myelin is associated with histological alterations and changes in the level of some specific CNS components. Suppression of the EAE episodes has been one of the major goals of research in this area. At this respect, the immunoregulatory mechanisms involved in EAE have been subject of studies carried out in our laboratory. Intraperitoneal (i.p.) treatment of Wistar rats with soluble bovine myelin (BM) or MBP but not with unrelated antigens (ovalbumin, or bovine muscle and hepatic tissues), 10 and 3 days previously to immunization with BM-CFA, showed a diminished incidence and severity of clinical disease. Analysis of the CNS of pretreated animals showed that the treatment prevented the diminution of MBP, glycosphingolipids and 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNPase) activity and the increase in esterified cholesterol characteristic of the acute stage of the disease. CNS meningeal and parenchymal infiltration with mononuclear cells and deposits of immunoglobulins in the infiltrated regions were also reduced. Concomitantly the treatment abrogated the cellular proliferative response to MBP that was highly positive in nontreated treated EAE animals, and produced changes in the autoimmune humoral response. On the other hand, we have also previously demonstrated that antibodies or T cells against MBP from animals with EAE have the property to recognize several neuronal proteins, among them the synaptosomal protein synapsin I. These antibodies and T cells that bind both antigens MBP and synapsin correlate with the appearance of the clinic symptoms of EAE. Taking into account this immunological crossreactivity we also treated rats with a bovine synaptosomal fraction previously to the active induction of EAE. This treatment also diminished the incidence and severity of EAE, reverted the appearance of CNS histological and biochemical alterations and produced changes in the autoimmune humoral response against the encephalitogenic MBP similarly to the previously described suppression mediated by myelin antigens.
In order to characterize the myelin and synaptosomal mediated suppression processes, we examined the response to MBP of lymph node mononuclear cells derived from treated animals by proliferation assay and analysis of the cytokine secretion pattern. Cells from sick non-treated EAE rats showed proliferation to MBP and secretion of IL-2. Specific cells to MBP are also indeed present in animals treated with BM or the synaptosomal fraction but they showed a reduction of IL-2 release. Finally, total lymph node cells from treated animals were able to modulate the clinical symptoms of EAE when they were adoptively transferred to naive animals, previously to the induction of the disease. These results indicate that suppression of clinical and biochemical EAE alterations induced by intraperitoneal treatment with myelin as well as synaptosomal antigens involve an active suppression mechanism, and suggest that antigen-driven bystander suppression could be a mechanism by which synaptosomal proteins suppress the response against myelin antigens.
