The objectives 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 (mal-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 defivatized 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 the long-term treatment of immune disorders.Awardee's statement of the potential commercial applications of the research:This research has the commercial potential of identifying and developing novel, small synthetic compounds for the treatment of allograft rejection, autoimmune disease, and arthritis. These molecules should modify disease processes and be relatively safe and easy to manufacture, suggesting that they should have excellent commercial potential.National Institute of Allergy and Infectious Diseases (NIAID)
