Recombinant T-cell Receptor Ligands for Treatment of Uveitis

描述(申请人提供)：葡萄膜炎是一组炎症性眼病，通常与潜在的自身免疫性疾病过程有关。据目前估计，在美国，每年每100,000人中有17-52人会患葡萄膜炎，每年总计超过38,000例新病例。据进一步估计，美国10%至15%的失明是由于葡萄膜炎造成的。眼部自身抗原的免疫反应在葡萄膜炎的发病机制中起着核心作用，并受人类白细胞抗原(HL A)基因座的遗传控制。该项目的目标是开发治疗自身免疫性葡萄膜炎的治疗药物，以控制葡萄膜炎患者亚群特有的T细胞免疫反应。该项目是OHSU和病毒基因组公司的合作项目，病毒基因组公司是一家波特兰生物技术公司，拥有重组T细胞受体配体(RTLS)治疗技术的独家许可证。这种新药是一种新的分子，由人类白细胞抗原-DR2的a1b1结构域组成，作为单链连接到抗原肽上。在多发性硬化症的实验模型中，RTLS被发现抑制T细胞反应，这为RTLS在其他自身免疫性疾病中的测试和应用提供了基础，如自身免疫性葡萄膜炎。我们对自身免疫性前葡萄膜炎(AAU)治疗的初步研究表明RTLS在葡萄膜炎患者中有临床应用价值。此阶段STTR应用的目的是确定RTLS治疗Lewis大鼠急性和复发性自身免疫性葡萄膜炎的有效性。这些发现将为葡萄膜炎患者RTL的临床前和I期临床研究提供合理的依据。我们提出了以下具体目标：1.利用RTLS确定临床大鼠AAU的有效治疗方案。2.检测RTLS对Lewis大鼠复发性前、后葡萄膜炎的抑制作用。

DESCRIPTION (provided by applicant): Uveitis is a group of inflammatory eye diseases, often associated with an underlying autoimmune disease process. It is currently estimated that each year in the United States, from 17-52 out of every 100,000 persons will develop uveitis, totaling over 38,000 new cases per year. It is further estimated that 10% to 15% of the blindness in the United States is due to uveitis. Immune responses to ocular autoantigens play a central role in the pathogenesis of uveitis and are genetically controlled by specific human leukocyte antigen (HLA) loci. The goal of this project is to develop therapeutic drugs for the treatment of autoimmune uveitis that can control T cell immune responses characteristic of a subset of uveitic patients. This project is a collaborative work between OHSU and Virogenomics, a Portland biotechnology company that holds an exclusive license for Recombinant T-cell Receptor Ligands (RTLs) therapeutic technology. This new drug is a novel molecule consisting of the a1b1 domains of HLA-DR2 as a single chain that is linked to an antigenic peptide. RTLs have been found to inhibit T-cell responses in experimental models of multiple sclerosis, which has provided a basis for testing and applying RTLs in other autoimmune diseases, such as autoimmune uveitis. Our preliminary studies of treatment of autoimmune anterior uveitis (AAU) suggest a clinical application for RTLs in uveitic patients. The objective of this Phase I STTR application is to determine the effectiveness of RTLs in treating established acute and recurrent autoimmune uveitis in Lewis rats. These findings will provide rational basis for preclinical and Phase I clinical studies of the RTLs in uveitis patients. We propose the following specific aims: 1. To determine an effective treatment regimen for clinical rat AAU using RTLs. 2. To determine the abilities of RTLs to inhibit recurrent anterior and posterior uveitis in Lewis rats.