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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023444-07
Application #
3406934
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1987-01-01
Project End
1994-12-31
Budget Start
1993-01-01
Budget End
1993-12-31
Support Year
7
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Vandenbark, Arthur A; Offner, Halina (2008) Critical evaluation of regulatory T cells in autoimmunity: are the most potent regulatory specificities being ignored? Immunology 125:1-13
Vandenbark, Arthur A; Culbertson, Nicole E; Bartholomew, Richard M et al. (2008) Therapeutic vaccination with a trivalent T-cell receptor (TCR) peptide vaccine restores deficient FoxP3 expression and TCR recognition in subjects with multiple sclerosis. Immunology 123:66-78
Polanczyk, Magdalena J; Hopke, Corwyn; Vandenbark, Arthur A et al. (2007) Treg suppressive activity involves estrogen-dependent expression of programmed death-1 (PD-1). Int Immunol 19:337-43
Adamus, Grazyna; Burrows, Gregory G; Vandenbark, Arthur A et al. (2006) Treatment of autoimmune anterior uveitis with recombinant TCR ligands. Invest Ophthalmol Vis Sci 47:2555-61
Wang, Chunhe; Chou, Yuan K; Rich, Cathleen M et al. (2006) AlphaB-crystallin-reactive T cells from knockout mice are not encephalitogenic. J Neuroimmunol 176:51-62
Polanczyk, Magdalena J; Hopke, Corwyn; Vandenbark, Arthur A et al. (2006) Estrogen-mediated immunomodulation involves reduced activation of effector T cells, potentiation of Treg cells, and enhanced expression of the PD-1 costimulatory pathway. J Neurosci Res 84:370-8
Offner, Halina; Vandenbark, Arthur A (2005) Congruent effects of estrogen and T-cell receptor peptide therapy on regulatory T cells in EAE and MS. Int Rev Immunol 24:447-77
Offner, Halina; Subramanian, Sandhya; Wang, Chunhe et al. (2005) Treatment of passive experimental autoimmune encephalomyelitis in SJL mice with a recombinant TCR ligand induces IL-13 and prevents axonal injury. J Immunol 175:4103-11
Bourdette, D N; Edmonds, E; Smith, C et al. (2005) A highly immunogenic trivalent T cell receptor peptide vaccine for multiple sclerosis. Mult Scler 11:552-61
Polanczyk, Magdalena J; Hopke, Corwyn; Huan, Jianya et al. (2005) Enhanced FoxP3 expression and Treg cell function in pregnant and estrogen-treated mice. J Neuroimmunol 170:85-92

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