DERIVATIZED POLY-LYSINES AS IMMUNOSUPPRESSIVE AGENTS

此应用程序的目标是优化并开始 化学衍生的赖氨酸聚合物的药物开发 用作治疗移植排斥、自身免疫 疾病或关节炎。 这种衍生的聚合物已经显示出 抑制巨噬细胞上II（Ia）类分子的表达。 具体而言，我们将：1）验证马来酰化聚-L-赖氨酸（maI-PLL） 抑制单核细胞/巨噬细胞的抗原呈递; 2）确定 maI-PLL的细胞特异性; 3）优化衍生化的聚赖氨酸， 长度、衍生化密度、酰基要求，以及 赖氨酸的立体化学要求;和4）测试优化的版本 在同种异体移植物识别的动物模型中的衍生化聚赖氨酸。 将通过测量增殖来测定体外抗原呈递 淋巴细胞对同种异体抗原或回忆抗原的反应。 蜂窝 特异性将通过检查衍生化的 多聚赖氨酸对中性粒细胞，淋巴细胞， 成纤维细胞和内皮细胞。 同种异体移植物的体内测定 识别将测量移植物抗宿主（GVH）反应和皮肤移植物 接受老鼠 衍生化的聚赖氨酸可以具有商业上的 作为新型安全、相对便宜和易于制造的潜在用途， 用于长期治疗免疫疾病的有效药剂。

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.