Rheumatoid arthritis is a chronic inflammatory disease of diarthrodial joints. In preliminary studies we find that 50% of RA patients produce significant T cell responses to type II collagen (CII). Our hypothesis, that an antigen-driven autoimmune process mediates articular injury, is based on our findings that the oral administration of CII to arthritis patients in our open label trials resulted in favorable alterations in the cytokine profile measured. These data support the view that autoimmunity to an antigen(s) such as CII in cartilage plays a major role in the pathogenesis of the disease. We have used humanized mice bearing DRB1*0101 and DRB1*0401 transgenes and the collagen- induced arthritis (CIA) model to develop a collagen-based immunotherapy. By using proliferation and cytokine assays, we found that the core of the immunodominant determinant presented to murine T-cells by both DR1 and DR4 in Tg mice is CII263-270 (FKGEQGPK). Subsequently, a synthetic analog peptide was developed CII 263-273 (F263N, E266D) (A12) that was found to induce a profound suppression of CIA when administered after autoimmune arthritis has been established. Based on these data, we propose the following hypothesis: Interaction of the A12 analog peptide/APC complex with TCR leads to a unique signaling pathway, very likely involving phosphorylation of Syk rather than ZAP 70. The resulting cascade of signaling events induces predominantly Th2 cytokines and ultimately suppression of arthritis. We propose the following aims: 1) Identify T-cell signaling pathways activated by A12 and compare them with pathways induced by the wild type CII-peptide. 2) Characterize the inhibitory T cells induced by A12 and ascertain how this selected population can inhibit immunity to CII and autoimmune arthritis. 3) Determine the role of post-translational modifications in enhancing the efficacy of the A12 analog in suppressing immunity to CII and arthritis. These studies will determine what intracellular signaling pathways are triggered by A12, how these differ from those triggered by the unaltered peptide ligand and intact CII, and the consequences of this alteration on T cell phenotype. Information gained from these murine studies will provide preliminary data necessary for understanding how RA patients can successfully be treated with A12.

Public Health Relevance

This R01 is a new application in which we use humanized mice bearing DRB1*0101 and DRB1*0401 transgenes and the collagen-induced arthritis (CIA) model to develop a collagen-based immunotherapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR055661-04
Application #
8243697
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mao, Su-Yau
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$445,187
Indirect Cost
$144,385
Name
University of Tennessee Health Science Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Myers, Linda K; Cullins, David L; Park, Jeoung-Eun et al. (2015) Peptide ligand structure and I-Aq binding avidity influence T cell signaling pathway utilization. Clin Immunol 160:188-97
Tang, Bo; Kim, Seunghyun; Hammond, Sarah et al. (2014) Characterization of T cell phenotype and function in a double transgenic (collagen-specific TCR/HLA-DR1) humanized model of arthritis. Arthritis Res Ther 16:R7
Brown, Monica; Postlethwaite, Arnold E; Myers, Linda K et al. (2012) Supernatants from culture of type I collagen-stimulated PBMC from patients with cutaneous systemic sclerosis versus localized scleroderma demonstrate suppression of MMP-1 by fibroblasts. Clin Rheumatol 31:973-81
Kimata, Masaru; Cullins, David L; Brown, Monica L et al. (2012) Characterization of inhibitory T cells induced by an analog of type II collagen in an HLA-DR1 humanized mouse model of autoimmune arthritis. Arthritis Res Ther 14:R107
Park, Jeoung-Eun; Cullins, David; Zalduondo, Lillian et al. (2012) Molecular basis for T cell response induced by altered peptide ligand of type II collagen. J Biol Chem 287:19765-74
Myers, Linda K; Cullins, David L; Brand, David D et al. (2011) T cells stimulated with an analog peptide of type II collagen require the Fc receptor ýý-chain to secrete interleukin-4 and suppress autoimmune arthritis in mice. Arthritis Rheum 63:2661-70
Tang, Bo; Cullins, David L; Zhou, Jing et al. (2010) Modulation of collagen-induced arthritis by adenovirus-mediated intra-articular expression of modified collagen type II. Arthritis Res Ther 12:R136
Tang, Bo; Zhou, Jing; Park, Jeoung-Eun et al. (2009) T cell receptor signaling induced by an analog peptide of type II collagen requires activation of Syk. Clin Immunol 133:145-53