Induction of immune tolerance to self-antigens can ameliorate systemic autoimmune diseases such as lupus, anti-glomerular basement membrane glomerulonephritis and Goodpasture's syndrome in experimental models. Current approaches of autoantigen-specific Th cell tolerance induction, however, are cumbersome and expensive, as they require multiple intravenous injections of large doses of antigenic peptides; such approaches usually confer a limited and short-lasting therapeutic benefit in systemic autoimmune diseases. To overcome these limitations, we will develop a minigene approach of in vivo peptide delivery. Because antigens delivered as plasmid DNA tend to be 'immunogenic', and successful therapy depends on tolerizing Th cells, this application will explore how gene delivery of antigens can be modified to induce tolerance in CD4+ Th cells in vivo. Our hypothesis is that minigenes that encode self-peptides can be administered in ways that induce tolerance in peptide-specific autoreactive Th cells. Specifically, we will test if the minigenes that encode self-peptides specifically tolerize peptide-specific, MHC class II-restricted CD4+ Th cells that could otherwise provide help for the production of autoantibodies, if they: a) are administered orally or i.v. in high doses; b) encode multiple tandem repeats of a single epitope; or c) encode multiple tandem repeats of multiple epitopes. We will explore these possibilities using a mouse model of immune-mediated glomerulonephritis and peptides derived from the VH region of anti-DNA mAbs or nucleosome core histones. Tolerance induction in autoreactive T helper cells may ameliorate autoantibody-mediated diseases such as lupus, anti-glomerular basement membrane glomerulonephritis and Goodpasture's syndrome. The methods developed for the induction of T cell tolerance may have implications for the vaccination and treatment of various immune-mediated disorders.
