Over the previous funding period, a detailed analysis of the interaction between peptide and MHC molecules was made. During the course of those investigations, a novel mechanism by which analogs of peptide antigens inhibit the recognition of those antigens by T cells was made. It was found that certain antigen analogs not only competed with antigen for binding to MHC, but the antigen analog/MHC complexes could also compete with antigen/MHC complexes for binding to the T cell receptor. This application extends the observations on """"""""T-cell receptor antagonism"""""""" to explore the following issues: First, a series of experiments to examine the potential use of antigen analogs to intervene in the course of an autoimmune disease will be performed. To do this, the capacity of one or a few analogs to inhibit polyclonal antigen-specific responses needs to be established. Next, the capacity of such analogs to inhibit an in vivo disease process will be evaluated, using experimental allergic encephalitis as the model. Since the potential medical use of analogs is dependent upon knowledge of the nature of specific autoantigens involved in the pathogenesis of autoimmune disease, an effort will be made to identify the autoantigens involved in the NOD mouse model of diabetes. The relationship between T cell receptor antagonism elicited by antigen analogs and the capacity of analogs to induce incomplete stimulation of T cells (partial anergy), as described by Paul Allen, will also be assessed. Specifically, questions concerning the structural relationship of analogs that are TCR antagonists and those that are partial agonists will be defined, as will the capacity of these different analogs to elicit early signaling events such as tyrosine phosphorylation. Finally, the analysis of the biologic effects of antigen analogs will also be evaluated in a TCR transgenic system. The structural relationship of analogs that stimulate peripheral T cells and those that induce positive and negative selection in the thymus will be analyzed. This will allow an evaluation of an affinity hypothesis to explain thymic -differentiation events.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI018634-14
Application #
2003239
Study Section
Immunobiology Study Section (IMB)
Project Start
1988-08-01
Project End
1998-12-31
Budget Start
1997-01-01
Budget End
1997-12-31
Support Year
14
Fiscal Year
1997
Total Cost
Indirect Cost
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Yang, Wen; Grey, Howard M (2003) Study of the mechanism of TCR antagonism using dual-TCR-expressing T cells. J Immunol 170:4532-8
Kimachi, Kazuhiko; Sugie, Katsuji; Grey, Howard M (2003) Effector T cells have a lower ligand affinity threshold for activation than naive T cells. Int Immunol 15:885-92
Huang, Jianyong; Lo, Pei-Fen; Zal, Tomasz et al. (2002) CD28 plays a critical role in the segregation of PKC theta within the immunologic synapse. Proc Natl Acad Sci U S A 99:9369-73
Wang, Rongfang; Wang-Zhu, Yiran; Grey, Howard (2002) Interactions between double positive thymocytes and high affinity ligands presented by cortical epithelial cells generate double negative thymocytes with T cell regulatory activity. Proc Natl Acad Sci U S A 99:2181-6
Huang, J; Sugie, K; La Face, D M et al. (2000) TCR antagonist peptides induce formation of APC-T cell conjugates and activate a Rac signaling pathway. Eur J Immunol 30:50-8
Wang, R; Wang-Zhu, Y; Gabaglia, C R et al. (1999) The stimulation of low-affinity, nontolerized clones by heteroclitic antigen analogues causes the breaking of tolerance established to an immunodominant T cell epitope. J Exp Med 190:983-94
Zugel, U; Wang, R; Shih, G et al. (1998) Termination of peripheral tolerance to a T cell epitope by heteroclitic antigen analogues. J Immunol 161:1705-9
Rogers, P R; Grey, H M; Croft, M (1998) Modulation of naive CD4 T cell activation with altered peptide ligands: the nature of the peptide and presentation in the context of costimulation are critical for a sustained response. J Immunol 160:3698-704
Wang, R; Nelson, A; Kimachi, K et al. (1998) The role of peptides in thymic positive selection of class II major histocompatibility complex-restricted T cells. Proc Natl Acad Sci U S A 95:3804-9
Kimachi, K; Croft, M; Grey, H M (1997) The minimal number of antigen-major histocompatibility complex class II complexes required for activation of naive and primed T cells. Eur J Immunol 27:3310-7

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