COLLAGEN PEPTIDES AND SUPPRESSION OF COLLAGEN ARTHRITIS

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DESCRIPTION: (Adapted from the applicant's abstract) - Prior work of the applicant on the CIA mouse model demonstrated that the CB11 collagen II peptide contained the active site for this induction in residues 245-270 (A2 peptide), and modeled an analog peptide, A9, with substitutions in three amino acids, which can downregulate the severity of arthritis when co-administered with Collagen II(CII), or after induction of the disease. Two of the amino acids, 260 and 263 participate in peptide binding to the MHC molecule and residue 261 interacts with the T-cell receptor (TCR). Further preliminary data indicate that Collagen II-sensitized spleen and lymph node cells produce increased amounts of Interleukin-4 (IL-4) and Interleukin-10 (IL-10) when challenged with the A9 peptide as compared to the A2 peptide. The hypothesis to be tested in this application is that the A9 effect on CIA is mediated through polarization of the specific immune response to a predominant Th2 profile, and that this polarization is caused by changes in the affinity between either MHC and peptide or MHC/peptide interaction with the TCR leading to altered T cell signaling and, consequently, the production of cytokines. The specific aims are: 1) To identify the structural characteristics of the analog peptide A9 that mediate its modulation of the immune response to CII and CIA; 2) determine whether encoding the A9 substitutions within the triple helical CII increases the efficacy in inhibiting the autoimmune response in CIA; 3) determine whether the suppression of CIA produced by A9 administration is dependent on IL-10 or IL-4 secretion, and 4) determine the mechanism by which A9 alters T cell function by analyzing signaling pathways involved in T cell activation.