Abstract

The objective of this project is to identify, characterize and manipulate the HLA-encoded parameters associated with susceptibility to rheumatoid arthritis (RA). Our focus is on the """"""""shared epitope"""""""" --a specific cluster of MHC class II residues with immunologic and genetic properties implicated in RA. We propose to (1) modulate recognition of RA-associated HLA molecules through the design of specific peptide mimetics which recapitulate antibody and T cell receptor recognition directed to the shared epitope structure; and (2) analyze recognition of the shared epitope both in the context of.trimolecular interactions involving direct T cell receptor contact and also as a peptide, processed and re-presented as a traditional antigenic determinant.
These aims are based on the hypothesis that the genetic association of RA with the shared epitope sequence reflects an important immunologic event in pathogenesis which is an appropriate target and opportunity for novel therapeutic directions. A combination of experimental and computational approaches will be used to precisely identify the key structure/function components involved in recognition of the RA-associated shared epitope.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR037296-09A1
Application #
2079199
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1994-09-25
Project End
1997-08-31
Budget Start
1994-09-25
Budget End
1995-08-31
Support Year
9
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
Benaroya Research Institute at Virginia Mason
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98101

  Publications

Kuipers, H F; Nagy, N; Ruppert, S M et al. (2016) The pharmacokinetics and dosing of oral 4-methylumbelliferone for inhibition of hyaluronan synthesis in mice. Clin Exp Immunol 185:372-81
Kuipers, Hedwich F; Rieck, Mary; Gurevich, Irina et al. (2016) Hyaluronan synthesis is necessary for autoreactive T-cell trafficking, activation, and Th1 polarization. Proc Natl Acad Sci U S A 113:1339-44
Nagy, Nadine; Kaber, Gernot; Johnson, Pamela Y et al. (2015) Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis. J Clin Invest 125:3928-40
James, Eddie A; Rieck, Mary; Pieper, Jennifer et al. (2014) Citrulline-specific Th1 cells are increased in rheumatoid arthritis and their frequency is influenced by disease duration and therapy. Arthritis Rheumatol 66:1712-22
Pieper, J; Johansson, S; Snir, O et al. (2014) Peripheral and site-specific CD4(+) CD28(null) T cells from rheumatoid arthritis patients show distinct characteristics. Scand J Immunol 79:149-55
Ruppert, S M; Hawn, T R; Arrigoni, A et al. (2014) Tissue integrity signals communicated by high-molecular weight hyaluronan and the resolution of inflammation. Immunol Res 58:186-92
Evanko, Stephen P; Potter-Perigo, Susan; Bollyky, Paul L et al. (2012) Hyaluronan and versican in the control of human T-lymphocyte adhesion and migration. Matrix Biol 31:90-100
Bollyky, Paul L; Bogdani, Marika; Bollyky, Jennifer B et al. (2012) The role of hyaluronan and the extracellular matrix in islet inflammation and immune regulation. Curr Diab Rep 12:471-80
Snir, Omri; Rieck, Mary; Gebe, John A et al. (2011) Identification and functional characterization of T cells reactive to citrullinated vimentin in HLA-DRB1*0401-positive humanized mice and rheumatoid arthritis patients. Arthritis Rheum 63:2873-83
Gebe, John A; Falk, Ben; Unrath, Kellee et al. (2007) Autoreactive T cells in a partially humanized murine model of T1D. Ann N Y Acad Sci 1103:69-76

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