Human autoimmune diseases, of which more than 70 are known, afflict 5-10% of the US population. Some, such as rheumatoid arthritis, multiple sclerosis and diabetes occur at high frequency while others, such as pemphigus vulgaris have a low frequency. All of these diseases are linked to specific histocompatibilty proteins. The purpose of this application is to use mouse model of multiple sclerosis to investigate improvements in a drug which is currently in wide use for the therapy of this disease and to study in detail the mechanisms through which these drugs work. In particular we intend: 1. To investigate the use of a novel random amino acid copolymer poly(FYAK)n [a second generation Copaxone?1/2] for the amelioration of experimental autoimmune encephalomyelitis (EAE) in mice (as a model for their potential use in the amelioration of multiple sclerosis, MS) by: a) fully characterizing copolymer- specific, antigen-non-specific regulatory T cell lines generated in response to the random amino acid copolymer poly(F, Y, A, K)n. These regulatory T cells appear to be different from those already described and their generation is a major mechanism through which the copolymers function, b) investigating the amelioration of EAE by poly(F, Y, A, KJ^n in new models, c) synthesizing and examining the properties of additional amino acid copolymers, for example poly(V, W, A, K)n and poly(V, Y, A, K)n, to optimize efficacy in EAE. 2. To investigate the use of a peptide 15mer of defined sequence (a third generation Copaxone?1/2) for the amelioration of EAE by: a) extending the studies of amelioration of EAE by the J5 peptide 15mer, including careful comparison with poly(F, Y, A, K)n and Copaxone in three different protocols termed vaccination, prevention and treatment;b) characterizing fully regulatory T cell lines and clones generated after immunization with the J5 peptide 15mer, similarly to the above studies with amino acid copolymers;c) investigating further modifications of the J5 peptide 15mer;d) synthesizing MHC class II tetramers binding the J5 peptide 15mer with which to measure the frequency of JS-specific regulatory T cells tissues and in peripheral blood. This method could provide a means of establishing the frequency with which the J5 peptide 15mer needs to be administered to achieve maximum therapeutic efficacy;e) generating regulatory T cells in vivo by targeting the J5 peptide 15merto immature dendritic cells in vivo;f) Tracking regulatory T cells in vivo using a polymorphic marker and multiphoton intravital microscopy. __

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049524-08
Application #
7637479
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Esch, Thomas R
Project Start
2001-09-01
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
8
Fiscal Year
2009
Total Cost
$412,020
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Koenig, Paul-Albert; Spooner, Eric; Kawamoto, Norio et al. (2013) Amino acid copolymers that alleviate experimental autoimmune encephalomyelitis in vivo interact with heparan sulfates and glycoprotein 96 in APCs. J Immunol 191:208-16
Kawamoto, Norio; Ohnishi, Hidenori; Kondo, Naomi et al. (2013) The role of dendritic cells in the generation of CD4(+) CD25(HI) Foxp3(+) T cells induced by amino acid copolymers. Int Immunol 25:53-65
Kovalchin, Joseph; Krieger, Jeffrey; Genova, Michelle et al. (2011) Macrophage-specific chemokines induced via innate immunity by amino acid copolymers and their role in EAE. PLoS One 6:e26274
Stern, Joel N H; Keskin, Derin B; Kato, Zenichiro et al. (2010) Promoting tolerance to proteolipid protein-induced experimental autoimmune encephalomyelitis through targeting dendritic cells. Proc Natl Acad Sci U S A 107:17280-5
Kato, Zenichiro; Stern, Joel N H; Nakamura, Hironori K et al. (2010) The autoimmune TCR-Ob.2F3 can bind to MBP85-99/HLA-DR2 having an unconventional mode as in TCR-Ob.1A12. Mol Immunol 48:314-20
Strominger, Jack L (2010) An alternative path for antigen presentation: group 1 CD1 proteins. J Immunol 184:3303-5
Yin, Hongen; Vistica, Barbara P; Chan, Chi-Chao et al. (2009) Inhibition of experimental autoimmune uveitis by amino acid copolymers. J Neuroimmunol 215:43-8
Zhang, Hong; Stern, Joel N H; Strominger, Jack L (2009) T cell receptors in an IL-10-secreting amino acid copolymer-specific regulatory T cell line that mediates bystander immunosuppression. Proc Natl Acad Sci U S A 106:3336-41
Stern, Joel N H; Keskin, Derin B; Zhang, Hong et al. (2008) Amino acid copolymer-specific IL-10-secreting regulatory T cells that ameliorate autoimmune diseases in mice. Proc Natl Acad Sci U S A 105:5172-6
Krzewski, Konrad; Chen, Xi; Strominger, Jack L (2008) WIP is essential for lytic granule polarization and NK cell cytotoxicity. Proc Natl Acad Sci U S A 105:2568-73

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