T-CELL RECEPTOR ANTAGONIST PEPTIDES ARE HIGHLY EFFECTIVE INHIBITORS OF EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS

The feasibility of using T cell receptor (TcR) antagonist peptides to inhibit autoimmune disease has been examined. First, the fine antigeni c structure of the I-A(S)-restricted encephalitogenic determinant prot eolipid protein (PLP) 139-151 has been analyzed. It was found that res idues 145 and 148 were I-A(S) anchor residues, and residue 144 appeare d to be especially critical in T cell activation. Residues 142, 143, 1 46, and 147 were found to be crucial for activation of some, but not a ll, of the T cells studied. Next, good I-A(S)-binding nonantigenic ana logs were tested for TcR antagonism. Accordingly, several single subst itution analogs were identified which could act as TcR antagonists. Mo reover, when two such analogs were combined, the resulting TcR antagon ist pool inhibited most of the PLP 139-151-specific T cell clones in v itro. When the efficacy of this TcR antagonist pool in inhibiting EAE induction in vivo was examined, it was found that the analog pool was a remarkably potent inhibitor of disease induction. The TcR antagonist pool was approximately 10-fold more potent than our best major histoc ompatibility complex blocker and was still capable of significant inhi bition when injected in equimolar amounts with the encephalitogenic PL P 139-151 determinant.