Suppression of Collagen Induced Arthritis with Altered Peptide Ligands

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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 FcRɣ, 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) Characterize the inhibitory T cells induced by A9 It is our belief that a definitive understanding of the mechanism(s) through which A9 suppresses arthritis will facilitate the development of improved treatments for RA.