Rheumatoid arthritis is a chronic inflammatory disease of diarthrodial joints. This systemic disease is characterized by chronic synovitis, sustained by an antigen-driven immune process against one or more proteins found in cartilage. Although several antigens have been proposed to be involved in the autoimmune response in RA, type II collagen (CII) has received the most attention as a candidate autoantigen. Collageninduced arthritis (CIA) is an experimental model with several similarities to RA and is induced by immunization of susceptible strains of mice with CII. We have used the animal model of CIA to develop a specific immunotherapy capable of selectively blocking autoimmunity without interfering with the beneficial functions of the immune system. Previously we have identified and characterized the dominant determinant on CII recognized by T cells and have shown that arthritis can be suppressed by an analog peptide (A9), which differs from the wild-type determinant by three amino acids. We hypothesize that a major mechanism by which the A9 analog peptide functions is to drive uncommitted CD4+ T cells toward a unique inhibitory phenotype. Unlike the recently described Treg cells, the A9-induced inhibitory T cell subset is characterized by increased expression of FcRc, signaling through an alternate pathway (i.e. Syk rather than Zap-70), and secretion of predominantly IL-4. To further explore the hypothesis, we propose the following Specific Aims: 1) Identify the structural characteristics of A9 that are responsible for modulation of the immune response to CII and CIA. 2) Characterentified and characterized the dominant determinant on CII recognized by T cells and have shown that arthritis can be suppressed by an analog peptide (A9), which differs from and aim #3. The new aims now include the original aim #1 and aim #2a. We believe that meaningful results toward these specific aims can be obtained within the two-year funding. The revised aims are as follows: A.
SPECIFIC AIMS Collagen-induced arthritis (CIA) is a model of inflammatory arthritis caused by immunizing susceptible strains of animals with type II collagen (CII), the major structural component of cartilage. We have used this model to develop a highly specific immunotherapy capable of down regulating an autoimmune response to CII. The immunotherapy was based on development of an analog peptide of the immunodominant epitope of CII. Using proliferation and cytokine assays, we found that the core of the immunodominant determinant of CII recognized by T cells from CIA susceptible I-Aq mice is CII260-270 (A2). Our hypothesis was that introducing critical alterations into the interaction between antigen presenting cells and potentially pathogenic T cells would suppress autoimmune arthritis. We synthesized and tested a number of peptides analogous to A2 but where amino acids within the epitope were substituted based on those found in the corresponding sites of nonarthritogenic type I collagen. We discovered that an analog peptide (A9) with amino acid substitutions made at positions 260 (I?A), 261 (A?B), and 263 (F?N) could profoundly suppress immunity to CII and arthritis. Other peptidesef that a definitive understanding of the mechanism(s) through which A9 suppresses arthritis will facilitate the development of improved treatments for RA.
In this application, we plan to use the collagen-induced arthritis (CIA) model to develop a collagen-based immunotherapy based on the use of altered peptide ligands. The purpose of the proposal is to delineate the mechanism of action of this therapy with the ultimate aim of developing new treatments for RA.
|Park, Jeoung-Eun; Rotondo, Jeffrey A; Cullins, David L et al. (2016) Characterization of the Syk-Dependent T Cell Signaling Response to an Altered Peptide. J Immunol 197:4569-4575|
|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|
|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|
|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|
|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|