RECOMBINANT MHC MOLECULES FOR TARGETED IMMUNOSUPPRESSION

用于靶向免疫抑制的重组 MHC 分子

• 批准号: 2867240
• 负责人: Peter R Rhode
• 金额: $ 10万
• 依托单位: ALTOR BIOSCIENCE. LLC
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-15 至 2000-01-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2867240
• 关键词: MHC class II antigen; chimeric proteins; drug design /synthesis /production; experimental allergic encephalomyelitis; gene expression; immunosuppressive; laboratory mouse; molecular cloning; multiple sclerosis; protein engineering; protein purification; recombinant proteins

The overall goal of this project to develop protein-based reagents for the targeted immunosuppression of human multiple sclerosis. These reagents will consist of novel recombinant single-chain (sc) forms of the class II/peptide complex designed to target autoreactive T helper cells. Our approach for generating these molecules is innovative in that the nature of the class II/peptide complex can be readily manipulated to alter T cell responses and that large amounts of homogeneous and well-defined molecules can be produced. To achieve our goal, we will clone and express different classes of genetically altered soluble sc-MHC class II/peptide fusion molecules. A number of these molecules are currently being produced in our laboratory. The immunosuppressive properties of these molecules will be tested in activation and anergy assays using mouse T cells and T cells isolated from MS patients. The molecules will also be tested for their ability to effect the initiation and differentiation of Th1 and Th2 responses and T cell-mediated autoimmune disease (EAE) in animal model systems. The results from these studies will provide useful information regarding immunosuppressive potential of the sc-MHC and will be useful in determining their efficacy in treating human T-cell mediated autoimmune diseases. PROPOSED COMMERCIAL APPLICATIONS: The goal of this proposal is to establish whether or single-chain MHC class II/peptide molecules are effective in specifically suppressing T-cell mediate immune responses in vitro and in antigen-immunized and autoimmune mouse model systems. The results of these studies could be used as a basis a therapeutic approach for treating human T cell-mediated autoimmune diseases, such as multiple sclerosis.

该项目的总体目标是开发基于蛋白质的试剂，用于人类多发性硬化症的靶向免疫抑制。这些试剂将由新型重组单链 (sc) 形式的 II 类/肽复合物组成，旨在靶向自身反应性 T 辅助细胞。我们产生这些分子的方法是创新的，因为可以很容易地操纵 II 类/肽复合物的性质来改变 T 细胞反应，并且可以产生大量同质且明确的分子。为了实现我们的目标，我们将克隆并表达不同类别的基因改变的可溶性 sc-MHC II 类/肽融合分子。我们的实验室目前正在生产许多这样的分子。这些分子的免疫抑制特性将通过小鼠 T 细胞和从多发性硬化症患者分离的 T 细胞进行激活和无反应性测定来测试。还将测试这些分子在动物模型系统中影响 Th1 和 Th2 反应以及 T 细胞介导的自身免疫性疾病 (EAE) 的启动和分化的能力。这些研究的结果将提供有关 sc-MHC 免疫抑制潜力的有用信息，并将有助于确定其治疗人类 T 细胞介导的自身免疫性疾病的功效。拟议的商业应用：本提案的目标是确定单链 MHC II 类/肽分子是否能有效地在体外以及抗原免疫和自身免疫小鼠模型系统中特异性抑制 T 细胞介导的免疫反应。这些研究的结果可以作为治疗人类 T 细胞介导的自身免疫性疾病（例如多发性硬化症）的治疗方法的基础。