T-CELL RECEPTOR PEPTIDES IN TREATMENT OF AUTOIMMUNE-DISEASE - RATIONALE AND POTENTIAL

The natural tendency in T cell-mediated autoimmune conditions to devel op focused antigen-specific responses that over-utilize certain T cell receptor (TCR) V region segments prompts the induction of anti-TCR-sp ecific T cells and antibodies that can inhibit the pathogenic T cells and promote recovery from disease, This natural regulatory network can be manipulated by injecting synthetic peptide vaccines that correspon d to segments of the over-expressed V genes, In experimental autoimmun e encephalomyelitis (EAE), an animal model for the human disease multi ple sclerosis (MS), the pathogenic T cells are directed at myelin comp onents, including basic protein (MBP), In some strains such as the Lew is rat and the PL/J mouse, the encephalitogenic BP-specific T cells ov erexpress a particular V region gene (V beta 8.2) in their TCR, In viv o administration of V beta 8.2 peptides in rats or mice can prevent an d treat EAE by boosting regulatory anti-V beta 8.2-specific T cells th at inhibit but do not delete the encephalitogenic specificities, This regulation is mediated by soluble factors, suggesting that the presenc e of regulatory TCR-specific T cells within the target organ (the cent ral nervous system) may inhibit not only the stimulating V beta 8.2+ T cells, but also bystander T cells bearing different V genes, Parallel studies in MS patients have revealed striking V gene biases among BP- specific T cell clones from some patients that provided a rationale fo r TCR peptide therapy, Injection of V beta 5.2 and V beta 6.1 peptides boosted the frequency of TCR peptide-specific T cells and reduced res ponses to BP, in some cases with clinical benefit, indicating the pres ence of an anti-TCR regulatory network in humans that may also be mani pulated with TCR peptide therapy. (C) 1996 Wiley-Liss, Inc.