The major histocompatibility complex influences myelin basic protein 63-88-induced T cell cytokine profile and experimental autoimmune encephalomyelitis* Polymorphism of the major histocompatibility complex (MHC) influences susceptibility to experimental autoimmune encephalomyelitis (EAE) induced by myelin basic protein (MBP) in rats. Current concepts relate such influences to the capacity of class I1 molecules to present relevant peptides to autoreactiveT cells. We have here analyzed the MHC influence on the immune response and the development of EAE after immunization with the immunodominant peptide MBP-63-88. Analysis of MHC-congenic LEWIS strains showed that RTla, RTIC and RT1' haplotypes are permissive for disease induction, whereas RTld and RTIU are resistant. All EAE responding strains showed peptide-specific proliferation and interferon (1FN)-y secretion, but no early significant tendency to express interleukin (IL-4) or transforming growth factor (TGF)-P mRNA in lymphocytes in response to the MBP 63-88, 7 days post immunization ( p i ) . Later, 14 days p.i., peptide-specific induction of IL-4 and TGF-p occurred in RT1' rats. Among the EAE non-responders strains, only the RTIU rats showed an immune response to MBP 63-88. This response, however, was qualitatively different from the immune response in the EAE-susceptible strains. Thus, there was no proliferation and only moderate IFN-y production in response to peptide, but in contrast, a significant and early peptide-induced IL-4 and TGF-f3 response was observed.The data suggest that the MHC-associated susceptibility to EAE is partly related to the ability to mount a TH1-like immune response while the MHC-associated EAE resistance may either be related to MBP peptide non-responsiveness or to peptide recognition and induction of a qualitatively different and disease down-regulatory immune response.