Immune regulatory effects of central nervous system antigens in culture

Evidence from several different experimental systems suggests that regulatory cells specific for self-antigens exist in the normal immune repertoire, and that these cells are necessary for maintenance of self-tolerance and prevention of autoimmune disease. We attempted to demonstrate the existence of regulatory cells specific for central nervous system (CNS) antigens in normal mice. We tested the effects of myelin basic protein (MBP), glial fibrillary acidic protein (GFAP) and a mixture of soluble brain proteins (SBP) on cultured splenocytes. MBP at 50 microg/ml inhibited antigen-driven proliferation and this suppressive effect could be partially blocked by neutralizing antibodies to transforming growth factor (TGF)-beta. MBP decreased expression of mRNA for the cytokines IL-2 and IFN-gamma, and slightly increased mRNA expression for TGF-beta. These effects did not appear to be mediated by regulatory cells specific for MBP, since MBP also suppressed proliferation in MBP-deficient shiverer mice and the suppressive effect could not be reproduced with selected MBP peptides. SBP at 250 microg/ml also inhibited antigen-driven proliferation, but this effect could not be blocked by neutralizing antibodies against IL-4, IL-10 or TGF-beta. SBP reduced expression of mRNA for IL-2, IL-10 and TGF-beta. These results are more consistent with the presence of a soluble inhibitory factor than with the action of SBP-specific regulatory cells. GFAP had no significant effect on proliferation. These results do not support the existence of regulatory cells specific for CNS antigens. Further investigation into non-antigen-specific mechanisms will be important in defining how autoimmune damage in the CNS is prevented.