Copolymer 1 acts against the immunodominant epitope 82-100 of myelin basicprotein by T cell receptor antagonism in addition to major histocompatibility complex blocking

The synthetic random amino acid copolymer Copolymer 1 (Cop 1, Copaxone, gla tiramer acetate) suppresses experimental autoimmune encephalomyelitis, slow s the progression of disability, and reduces relapse rate in multiple scler osis (MS), Cop 1 binds to various class II major histocompatibility complex (MHC) molecules and inhibits the T cell responses to several myelin antige ns, In this study we attempted to find out whether, in addition to MHC bloc king, Cop 1, which is immunologically cross-reactive with myelin basic prot ein (MBP), inhibits the response to this autoantigen by T cell receptor (TC R) antagonism. Two experimental systems, "prepulse assay" and "split APC as say," were used to discriminate between competition for MHC molecules and T CR antagonism. The results in both systems using T cell lines/clones from m ouse and human origin indicated that Cop 1 is a TCR antagonist of the 82-10 0 epitope of MBP, In contrast to the broad specificity of the MHC blocking induced by Cop 1, its TCR antagonistic activity was restricted to the 82-10 0 determinant of MBP and could not be demonstrated for proteolipid protein peptide or even for other MBP epitopes, Yet, it was shown for all the MBP 8 2-100-specific T cell lines/clones tested that were derived from mice as we ll as from an MS patient. The ability of Cop 1 to act as altered peptide an d induce TCR antagonistic effect on the MBP p82-100 immunodominant determin ant response elucidates further the mechanism of Cop 1 therapeutic activity in experimental autoimmune encephalomyelitis and MS.