The main goal of this project is to delineate the mechanism(s) of antigen- specific tolerance in collagen-induced arthritis (CIA) in mice. CIA is a widely accepted animal model of autoimmune arthritis sharing several important immunological, pathological and clinical features with rheumatoid arthritis. During the present funding period, it has been shown that predominant tolerogenic epitopes are located in a CNBr derived fragment of type II collagen (CB11). One of these has been identified as the peptide sequence of residues 260-270 of the a1(II) chain (CII 260-270). By the use of synthetic peptides representing CII 260-270 but containing site-directed substitutions, several critical residues within this epitope have been identified. In the present application, we propose to extend our observations to: 1) complete the characterization of CII 260-270 by examination of additional synthetic peptides containing amino acid substitutions at critical residues and to determine if additional T cell epitope(s) identified in Project #1 are tolerogenic; 2) develop cloned T cell lines reactive with CII 260-270 and capable of suppressing arthritis; 3) determine the T cell receptor (TcR) repertoire utilized by cells capable of inducing suppression; and 4) determine the mechanism of tolerance using transgenic mice bearing TcR which react with CII 260-270. Complete characterization of this epitope will allow us to design peptide agents which may disrupt the interactions of trimolecular complex of I-A molecule/peptide/TcR. Moreover, a definitive determination of TcR utilization in this system by the use of specific monoclonal antibodies against TcR Vb products, polymerase chain reaction and transgenic technology will enable us to design specific anti T cell therapy. The foundation of this project has carefully been laid during the past several years. We are now at the threshold of complete delineation of the structural determinants of CII that have the capacity to suppress arthritis, and elucidation of the mechanisms of tolerance to autoantigens in this important model of autoimmune arthritis. We believe these data will have important implications for therapy of autoimmune arthritis.
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