There are many regulatory and inductive influences on the generation and propagation of response to a self-antigen such as myelin basic protein (MBP). The form of the antigen, the nature of the antigen-presenting cell, the level of tolerance in the T cell repertoire under scrutiny, and members of antigen-based and T cell receptor (TCR)-based regulatory circuits are all directly involved. Aspects of these influences on the expressed T cell repertoire to MBP and at points, to another neuronal protein, proteolipid protein (=PLP), will be studied. A regulatory circuit comprised of a CD4+ T regulatory cell (a suppressor-induced cell) and a CD8+ T suppressor cell has been described in our laboratory, which acts to control the activity of the CD4+ effector T cells responsible for disease. In this proposal, one of the aims will be to study the role of the CD8+ T cell in this circuit--its specificity and regulatory target. TCR transgenic systems will be employed with low frequencies of T cells bearing the transgenic receptor. Likewise, regulation can be initiated by antigen, and although it also proceeds to engage the TCR idiopeptide-based circuit, we would like to study the T suppressor cell induced by suppressor T cell-inducing determinants on MBP. We will investigate the relationship between the form in which the antigenic determinant exists and the V gene usage in the TCR of the selected T cells. Two types of tolerance experiments will be undertaken. One of them has as its focus the subdominant and cryptic determinants on the self protein, MBP, and their importance in perpetuating the neurologic disease, experimental allergic encephalomyelitis. Further, the effectiveness of peptides in inducing tolerance during chronic phases of disease will be tested. We will explore how a change in the affinity of peptide ligands for the MHC molecule can affect the direction of T cell maturation and influence the proportion of Th1 of Th2 cells produced after antigenic stimulation. These studies should help to establish a clearer understanding and potential therapies for this autoimmune disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI028419-09S1
Application #
2862345
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1989-08-01
Project End
2000-07-31
Budget Start
1998-09-30
Budget End
1999-07-31
Support Year
9
Fiscal Year
1998
Total Cost
Indirect Cost
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Stevens, David B; Gold, Daniel P; Sercarz, Eli E et al. (2002) The Wistar Kyoto (RT1(l)) rat is resistant to myelin basic protein-induced experimental autoimmune encephalomyelitis: comparison with the susceptible Lewis (RT1(l)) strain with regard to the MBP-directed CD4+ T cell repertoire and its regulation. J Neuroimmunol 126:25-36
Ria, F; van den Elzen, P; Madakamutil, L T et al. (2001) Molecular characterization of the T cell repertoire using immunoscope analysis and its possible implementation in clinical practice. Curr Mol Med 1:297-304
Quinn, A; McInerney, M F; Sercarz, E E (2001) MHC class I-restricted determinants on the glutamic acid decarboxylase 65 molecule induce spontaneous CTL activity. J Immunol 167:1748-57
Quinn, A; Melo, M; Ethell, D et al. (2001) Relative resistance to nasally induced tolerance in non-obese diabetic mice but not other I-A(g7)-expressing mouse strains. Int Immunol 13:1321-33
Maverakis, E; van den Elzen, P; Sercarz, E E (2001) Self-reactive T cells and degeneracy of T cell recognition: evolving concepts-from sequence homology to shape mimicry and TCR flexibility. J Autoimmun 16:201-9
Moudgil, K D; Sercarz, E E (2000) The self-directed T cell repertoire: its creation and activation. Rev Immunogenet 2:26-37
Borghans, J A; De Boer, R J; Sercarz, E et al. (1998) T cell vaccination in experimental autoimmune encephalomyelitis: a mathematical model. J Immunol 161:1087-93
Drakesmith, H; O'Neil, D; Schneider, S C et al. (1998) In vivo priming of T cells against cryptic determinants by dendritic cells exposed to interleukin 6 and native antigen. Proc Natl Acad Sci U S A 95:14903-8
Sercarz, E E (1998) Immune focusing vs diversification and their connection to immune regulation. Immunol Rev 164:5-10
Kumar, V; Tabibiazar, R; Geysen, H M et al. (1995) Immunodominant framework region 3 peptide from TCR V beta 8.2 chain controls murine experimental autoimmune encephalomyelitis. J Immunol 154:1941-50

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