The goal of this program is to use specific myelin antigens to alter differentiation of autoreactive T cells, and to study the cellular and molecular mechanisms by which myelin antigens or altered forms of myelin antigens may shift the balance of pro-inflammatory cytokines from responding autoreactive T lymphocytes. To this end, three projects have been constructed: Project 1 (Kuchroo, V.K. Project Leader) will study the mechanism by which altered peptides of myelin proteolipid protein can either inhibit or enhance the autoimmunity of the CNS using the EAE model. In this project native encephalitogenic and altered peptide ligand (APL) specific TCR transgenic mice will be utilized to understand the mechanism by which APLs can shift the cytokine balance. Project 2 (Weiner, H.L Project Leader) will study the effect of feeding myelin antigens, altered forms of myelin antigens or co-polymer (Copaxone ) on the regulation of EAE. In this project Dr. Weiner will study the effect of changing the affinity of the peptides that have been altered either at the MHC residue or at the T cell contact residue, and determine the effect of these altered peptides in inhibiting or enhancing oral tolerance. In addition, this project will study the mechanisms of induction of regulatory T cells (Th3 type cells that produce TGF-beta) that are induced following oral administration of antigen, and also will study enhancement by oral tolerance by oral cytokines (IL-4, IL-10, IFN- tau). Project 3 (Hafler, D.A. Project Leader) will examine the effect of APLs in the induction of regulatory cytokines from human MBPp85-99 reactive T lymphocytes. This project examines whether APLs induce a new population of Th2 autoreactive cells or if they differentially signal pathogenic T cells and alter their differentiation. In addition, this project will examine whether Copaxone acts as an APL for MBP reactive T cell using combinatorial peptide libraries. The use of combinatorial libraries will also be used to define preferential antigens recognized by Copaxone reactive T cells. Projects 1 & 3 will have a consortium with Dr. S. Burakoff's laboratory at Dana Farber Cancer Institute, Boston to study the intracellular signaling events in T lymphocytes following crosslinking of TCRs with cognitive versus APLs. An immunopathology core will support projects 1 and 2. The three interdependent projects address a common theme: development of antigen specific, non-toxic therapy for the treatment of the CNS autoimmune disease-MS. Study of basic mechanisms in animal models and immune responses in MS patients as outlined above will help understanding towards reaching this goal.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Utz, Ursula
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Kitz, Alexandra; de Marcken, Marine; Gautron, Anne-Sophie et al. (2016) AKT isoforms modulate Th1-like Treg generation and function in human autoimmune disease. EMBO Rep 17:1169-83
Murugaiyan, Gopal; da Cunha, Andre Pires; Ajay, Amrendra K et al. (2015) MicroRNA-21 promotes Th17 differentiation and mediates experimental autoimmune encephalomyelitis. J Clin Invest 125:1069-80
Zhu, Chen; Sakuishi, Kaori; Xiao, Sheng et al. (2015) An IL-27/NFIL3 signalling axis drives Tim-3 and IL-10 expression and T-cell dysfunction. Nat Commun 6:6072
Van Haren, Keith; Tomooka, Beren H; Kidd, Brian A et al. (2013) Serum autoantibodies to myelin peptides distinguish acute disseminated encephalomyelitis from relapsing-remitting multiple sclerosis. Mult Scler 19:1726-33
Wu, Chuan; Pot, Caroline; Apetoh, Lionel et al. (2013) Metallothioneins negatively regulate IL-27-induced type 1 regulatory T-cell differentiation. Proc Natl Acad Sci U S A 110:7802-7
Rangachari, Manu; Kuchroo, Vijay K (2013) Using EAE to better understand principles of immune function and autoimmune pathology. J Autoimmun 45:31-9
Xiao, Sheng; Brooks, Craig R; Zhu, Chen et al. (2012) Defect in regulatory B-cell function and development of systemic autoimmunity in T-cell Ig mucin 1 (Tim-1) mucin domain-mutant mice. Proc Natl Acad Sci U S A 109:12105-10
Murugaiyan, Gopal; Beynon, Vanessa; Pires Da Cunha, Andre et al. (2012) IFN-? limits Th9-mediated autoimmune inflammation through dendritic cell modulation of IL-27. J Immunol 189:5277-83
Liu, Sue M; Sutherland, Andrew P R; Zhang, Zheng et al. (2012) Overexpression of the Ctla-4 isoform lacking exons 2 and 3 causes autoimmunity. J Immunol 188:155-62
Lozano, Ester; Dominguez-Villar, Margarita; Kuchroo, Vijay et al. (2012) The TIGIT/CD226 axis regulates human T cell function. J Immunol 188:3869-75

Showing the most recent 10 out of 128 publications