DERIVATIZED POLY-LYSINES AS IMMUNOSUPPRESSIVE AGENTS

此应用程序的目标是优化并开始 化学衍生赖氨酸聚合物的药物研究进展 用于治疗移植物排斥反应，自身免疫 疾病，或关节炎。这种衍生化聚合物已被证明 抑制巨噬细胞表达II(Ia)类分子。 具体地说，我们将：1)验证马来酸化多L赖氨酸(MAI-PLL) 抑制单核/巨噬细胞的抗原提呈；2)确定 MAI-PLL的细胞特异性；3)优化衍生化多赖氨酸 长度、衍生密度、酰基要求和 赖氨酸的立体化学要求；以及4)测试优化版本 在同种异体移植物识别的动物模型中衍生多赖氨酸。 体外抗原呈递将通过测量增殖来进行检测 淋巴细胞对同种异体抗原或召回抗原的反应。蜂窝 特异性将通过检查派生的影响确定 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检测 识别将测量移植物抗宿主(GVH)反应和皮肤移植 在大鼠体内的接受性。衍生的多赖氨酸可能具有商业价值 潜在的新的安全，相对便宜和易于制造，以及 长期治疗免疫疾病的有效药物。

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.