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.
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.
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