The objectives of this application are to optimize and begin the pharmaceutical development of chemically-derivatized polymers of lysine for use as therapeutics in the treatment of graft rejection, autoimmune diseases, or arthritis. Such derivatized polymers have been shown to inhibit the expression of class II (Ia) molecules on macrophages. Specifically, we will: 1) verify that maleylated poly-L-lysine (maI-PLL) inhibits antigen presentation by monocytes/macrophages; 2) determine the cellular specificity of maI-PLL; 3) optimize derivatized poly-lysine in terms of length, density of derivatization, acyl group requirements, and stereochemical requirements of the lysines; and 4) test optimized versions of derivatized poly-lysine in animal models of allograft recognition. Antigen presentation in vitro will be assayed by measuring proliferation of lymphocytes in response to alloantigens or recall antigens. Cellular specificity will be determined by examining the effects of derivatized poly-lysine on functional activities of neutrophils, lymphocytes, fibroblasts and endothelial cells. In vivo assays of allograft recognition will measure graft-versus-host (GVH) responses and skin graft acceptance in rats. Derivatized poly-lysines may have commercial potential as novel safe, relatively cheap and easy to manufacture, and efficacious agents for long-term treatment of immune disorders.
