Multiple sclerosis (MS) is a neurodegenerative demyelinating, disease of unknown etiology. MS plaques contain both CD4+ and CD8+ T-cells and susceptibility is linked to immune response genes, suggesting that MS occurs when autoreactive T-cells enter the central nervous system (CNS) and attack cells expressing myelin antigens. Myelin basic protein (MBP) is one likely target: for these T-cells because it is an abundant protein in the myelin sheath. Auto‑reactive CD4+ T-cells specific for MBP have been extensively studied in an animal model of MS, experimental allergic encephalomyelitis (EAE). EAE is induced by activating CD4+ T-cells through immunization of animals with MBP. Although this model demonstrates that MBP‑specific T-cells are present in the periphery of healthy animals, the investigators have shown that the repertoire of MBP‑specific T-cells in the periphery is strongly shaped by induction of immune tolerance to MBP in vivo. Some MBP‑specific T-cells are more prevalent in the periphery because they escape tolerance while other MBP‑specific T-cells are tightly regulated by tolerance. The mechanisms that induce tolerance to MBP, and how these mechanisms influence autoimmune disease, are unknown and are the focus of this application.
In Aim 1, they will use newly developed TCR transgenic mouse models specific for highly tolerogenic MHC class II‑associated epitopes of MBP to define tolerance mechanisms and their impact on disease susceptibility.
In Aims 2 and 3, they will investigate a new area: tolerance and autoimmune potential of MBP‑specific CD8+ cytotoxic T-cells (CTLs). Our recent data show that MBP‑specific CTLs are generated in vivo and regulated by tolerance induction. In this proposal, they show that these MBP‑specific CTLs induce a novel CNS autoimmune disease that differs from EAE and demonstrates new parallels to symptoms of MS. They will investigate mechanisms of tolerance that operate on these CTLs as well as their effector mechanisms and target cells within the CNS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035126-06
Application #
6393791
Study Section
Special Emphasis Panel (ZRG1-IMB (02))
Program Officer
Utz, Ursula
Project Start
1996-12-01
Project End
2005-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
6
Fiscal Year
2001
Total Cost
$342,000
Indirect Cost
Name
University of Washington
Department
Biochemistry
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Simmons, Sarah B; Pierson, Emily R; Lee, Sarah Y et al. (2013) Modeling the heterogeneity of multiple sclerosis in animals. Trends Immunol 34:410-22
Pierson, Emily; Simmons, Sarah B; Castelli, Luca et al. (2012) Mechanisms regulating regional localization of inflammation during CNS autoimmunity. Immunol Rev 248:205-15
Goverman, Joan M (2011) Immune tolerance in multiple sclerosis. Immunol Rev 241:228-40
McBeth, Christine; Seamons, Audrey; Pizarro, Juan C et al. (2008) A new twist in TCR diversity revealed by a forbidden alphabeta TCR. J Mol Biol 375:1306-19
Seamons, Audrey; Perchellet, Antoine; Goverman, Joan (2006) Endogenous myelin basic protein is presented in the periphery by both dendritic cells and resting B cells with different functional consequences. J Immunol 177:2097-106
Perchellet, Antoine; Stromnes, Ingunn; Pang, Jennifer M et al. (2004) CD8+ T cells maintain tolerance to myelin basic protein by 'epitope theft'. Nat Immunol 5:606-14
Seamons, Audrey; Sutton, Jennifer; Bai, Dina et al. (2003) Competition between two MHC binding registers in a single peptide processed from myelin basic protein influences tolerance and susceptibility to autoimmunity. J Exp Med 197:1391-7
Huseby, E S; Sather, B; Huseby, P G et al. (2001) Age-dependent T cell tolerance and autoimmunity to myelin basic protein. Immunity 14:471-81
Goverman, J (1999) Tolerance and autoimmunity in TCR transgenic mice specific for myelin basic protein. Immunol Rev 169:147-59
Loftus, C; Huseby, E; Gopaul, P et al. (1999) Highly cross-reactive T cell responses to myelin basic protein epitopes reveal a nonpredictable form of TCR degeneracy. J Immunol 162:6451-7

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