A series of analogue peptides have been generated, using as a template the core region of the OVA 323-339 peptide identified as critical in determining binding to I-Ad. Several of these "core extended" peptides had increased affinities for the I-Ad molecule compared to the native sequence, and were able to inhibit activation of an I-Ad-restricted T cell hybridoma in vitro. The induction of a T cell proliferative response to a peptide antigen could be inhibited by co-administration of core-extended peptide with antigen in the same adjuvant emulsion. Furthermore, inhibition also occurred when the inhibitor molecule was delivered separately one day before immunization. Finally, the induction of the autoimmune disease, experimental allergic encephalomyelitis (EAE), in susceptible mice could be reduced by the administration of a core-extended peptide with high affinity for the appropriate class II molecule. These findings have implications for the use of MHC antagonists in the control and treatment of MHC-associated autoimmune conditions in humans.