T cell receptor peptides in treatment of autoimmune disease: rationale and potential.
The natural tendency in T cell-mediated autoimmune conditions to develop focused antigen-specific responses that over-utilize certain T cell receptor (TCR) V region segments prompts the induction of anti-TCR-specific 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 correspond to segments of the over-expressed V genes. In experimental autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis (MS), the pathogenic T cells are directed at myelin components, including basic protein (MBP). In some strains such as the Lewis rat and the PL/J mouse, the encephalitogenic BP-specific T cells overexpress a particular V region gene (V beta 8.2) in the TCR. In vivo administration of V beta 8.2 peptides in rats or mice can prevent and treat EAE by boosting regulatory anti-V beta 8.2-specific T cells that inhibit but do not delete the encephalitogenic specificities. This regulation is mediated by soluble factors, suggesting that the presence of regulatory TCR-specific T cells within the target organ (the central 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 for 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 responses to BP, in some cases with clinical benefit, indicating the presence of an anti-TCR regulatory network in humans that may also be manipulated with TCR peptide therapy.
Vandenbark
A A
AA
Veterans Affairs Medical Center, New York, New York, USA.
Hashim
G A
GA
Offner
H
H
D000818:Animals; D000937:Antigen-Antibody Reactions; D001327:Autoimmune Diseases / Q000628:therapy*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000628:therapy; D000939:Epitopes; D006801:Humans; D051379:Mice; D009103:Multiple Sclerosis / Q000235:genetics / Q000628:therapy; D010446:Peptide Fragments / Q000627:therapeutic use*; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry*; D014611:Vaccination
D000939:Epitopes; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell