Rheumatoid arthritis (IRA) is a T cell mediated autoimmune disease that affects nearly 1% of the population worldwide. Collagen-induced arthritis (CIA) is an animal model for RA that can be induced in susceptible strains of mice by immunizing with type II collagen (CII). Susceptibility to CIA is associated with specific MHC class II molecules on the antigen presenting cells (APC) that present arthritogenic peptides from CII and acitvate CII specfic T cells. Complete activation of T cells requires additional signals delivered via CD28 interacting with the b7 ligands on the APC. Activated T cells subsequently express CTLA-4, which also binds the b7 ligands and terminate the immune response. Thus the b7:CD28/CTLA4 molecules serve as attractive targets for immunomodulation. Costimulatory blockade by CTLA4-1g suppresses multiple autoimmune diseases such as psoriasis and systemic lupus erythematosus (SLE). Studies in animal models suggest that the beneficial effect of CTLA4-1g many be compromised by the adverse effects of concomitant blockade of downregulatory b7:CTLA-4 interaction. Theoretically, a selective blockade of CD28 leaving the b7:CTLA4-1g interaction intact should preferentially suppress activated T cells. Recently, a peptide mimic of the ligand binding epitope of CD28 was shown to inhibit T cell responses. Structurally, the CD28 peptide adopted a polyproline type II (PPII) helical conformation found in regions of transient protein-protein interactions. In the present proposal knowledge derived from the interresidue interatomic distances in the human b7-1: CD152 complex, the residue-residue contact preferences and the propensity for residues in PP II helical conformation are integrated in the design of b7-competitive antagonist peptides (b7-CAP) such that the new peptides lower molecular mass, optimum PP II helical content in the context of ligand binding.
The specific aims are to determine the binding kinetics of the b7-CAPs to b7-1 and b7-2 and evaluate the preventive and therapeutic efficacy of the b7-CAPs and CD28 peptide mimics in DBA/1 Lac J mice induced CIA. ? ? ? ?
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