Immunization of Lewis rats with guinea pig myelin basic protein (GP-BP) induces experimental autoimmune encephalomyelitis (EAE), a presynaptic disease mediated by T cell clones directed at a single immunodominant epitope corresponding to GP-BP residues 72-89. T cells responding to this epitope express antigen receptors which utilize preferentially a specific Valpha:ta gene combination. Immunity directed against common T cell receptor epitopes present on encephalitogenic specificities offers the hope of exquisitely selective immunosuppression. We have found that vaccination with attenuated encephalitogenic T cells can induce protection against EAE involving immune mechanisms directed in part at the T cell receptor. However, induction of such regulatory immunity with intact T cells is precise due to the variety of competing cell surface antigens. The overall goal of this proposal is to define peptide sequence of the T cell receptor od encephalitogenic clones that can induce protective immunity against EAE. Using cDNA probes, we have determined the nucleotide and amino acid sequence for the Lewis rat T cell receptor alpha and beta chains of encephalitogenic T helper cells. Using expression vectors, we have produced relatively large quantities of T cell receptor proteins which can be used as immunogens. Additionally, we have synthesized peptides with sequences corresponding to the complementarity determining regions (CDR) of encephalitogenic T cell receptor chains, thought to be important in ligand binding. Direct immunization of naive rats with T cell receptor sequences should induce both cellular and humoral responses directed specifically at the Valpha or Vbeta T cell receptor peptides used preferentially by encephalitogenic T cells, In this proposal, we will evaluate the immunogenicity of attenuated encephalitogenic T cells and T cell receptor proteins and peptides, document the properties of T cells and antibodies directed against these proteins, and evaluate the efficacy of such anti-T cell receptor immunity in regulating the development of EAE. Successful induction of regulatory T cells or antibodies and identification of the relevant antigenic regions within T cell receptor (eg. the CDR loops) could lead to a peptide vaccine which may have prophylactic and therapeutic values against EAE and other autoimmune diseases where preferential TcR V gene combinations can be identified.
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