Development of TCR-CDR3 vaccine for multiple sclerosis

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Autoimmune encephalitogenic T cells tend to express limited sequence motifs in the CDR3 regions of T cell receptor alpha - and beta -chains (Int. Immunol. 6 : 947, 1994). We have recently reported that a peptide sequence from alpha -chain CDR3 of an encephalitogenic clone 4b. 14a would enhance the severity of experi-mental autoimmune diseases including experimental autoimmune encephalomyelitis (EAE), adjuvant arthritis or autoimmune diabetes, regardless of the antigen/MHC specificities (J.Neurosci. Res. 45 : 706-713, 1996). Here we clarify that the observed augmentation of autoimmune encephalomyelitis is probably mediated by a regulatory T cell clone reactive to the CDR3 peptide. We reached the conclusion by generat-ing T cell hybridomas reactive to the peptide and performing adoptive transfer experiments with CDR3 reactive T cells. Of particular note, the single strand conformation polymorphism (SSCP) analysis for T cell clonorype revealed that CDR3 reactive clone is in vivo expanded and present among the CD25^+T cells in naive SJL/J mice. This implies that a single T cell clone reactive to a TCR CDR3 peptide is in a state of persistent activation and expansion. Thus antigen nonspecific between autopathogenic T cells and the regulatory T cells. The result could lead to the development of a new TCR vaccine. In fact, and altered form of the CDR3 peptide may induce inactivation of the regulatory clone, leading to the down-regulation of EAE.Such a vaccine should be of practical value, since it could be effective for different diseases and manage to treat disease even after occurrence of epitope-spreading. We are now focusing on the identifica-tion of an appropriate ligand for the CDR3 reactive regulatory T cells.