Human MHC Class II Constructs For Autoimmume Therapy

用于自身免疫治疗的人类 MHC II 类构建体

• 批准号: 6920763
• 负责人: GREGORY George BURROWS
• 金额: $ 35.25万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6920763
• 关键词: MHC class II antigen; T cell receptor; T lymphocyte; autoimmune disorder; biological signal transduction; calcium flux; clinical research; drug design /synthesis /production; human subject; immunoconjugates; immunopharmacology; leukocyte activation /transformation; ligands; phospholipase C; receptor binding; recombinant proteins; surface plasmon resonance

DESCRIPTION (provided by investigator): The goal of this research is to understand and control the activation of pathogenic T cells. Activation of T cells is a multi-step process initiated by co-ligation of antigen-specific T cell receptor (TCR) and co-receptor CD4 with the MHC class II/peptide complex present on antigen presenting cells (APC) (signal I), and includes co-stimulation through T cell surface molecules such as CD28 (signal 2). Our working hypothesis is that T cells can be controlled by regulating the context in which MHC/peptide interacts with the TCR. In order to test this hypothesis we have recently developed a family of novel Recombinant TCR ligands (RTLs) derived from HLADR2 alpha-1 and beta-l domains, with and without a covalently linked peptide antigen. The RTL technology was first described in the context of the animal model of multiple sclerosis, EAE (experimental autoimmune encephalomyelitis). RTLs inhibited activation of pathogenic MBP72-89 reactive T cells and could be used to prevent and treat EAE. The potential of these molecules in the treatment of human autoimmune disease provides strong rationale to develop human RTLs and further characterize the mechanism by which the molecules regulate CD4+ pathogenic T cells. We propose to 1) Characterize human RTLs biochemically to enhance the pharmacological utility of the molecules; 2) Study the effect RTLs have on immune synapse formation and quantitate the binding interactions between RTL and TCR using surface plasmon resonance (Biacore); and 3) Characterize the molecular mechanism(s) by which RTLs effect signal transduction and T cell activation, to define the time-frame and context within which RTL treatment can alter effector cells in an antigen-specific manner. Completion of this proposal will identify unique points of intervention for controlling T cells and in turn the T cell immune response and repertoire. Understanding how these unique, rationally engineered drugs work will provide a solid foundation for pharmacological intervention in CD4+ T cell mediated autoimmune diseases.

描述(由调查人员提供)：本研究的目标是 了解和控制致病T细胞的激活。激活T细胞 细胞是一个由抗原特异性T细胞共连接启动的多步骤过程 细胞受体(TCR)和辅受体CD4与MHC II类/肽复合体 存在于抗原提呈细胞(APC)(信号I)上，包括 通过CD28等T细胞表面分子共同刺激(信号2)。我们的 工作假说是T细胞可以通过调节上下文来控制 其中MHC/肽与TCR相互作用。 为了验证这一假设，我们最近开发了一系列小说 来自HLADR2α-1和β-L结构域的重组TCRL， 具有和不具有共价连接的多肽抗原。RTL技术是 首次在多发性硬化症动物模型的背景下描述，EAE (实验性自身免疫性脑脊髓炎)。RTLS抑制血管内皮细胞的激活 致病MBP72-89反应性T细胞可用于预防和治疗 EAE。这些分子在治疗人类自身免疫方面的潜力 疾病为人类RTL的发展提供了强有力的理由，并进一步 描述分子调节CD4+致病T细胞的机制 细胞。我们建议1)从生物化学的角度表征人类的RTL，以增强 分子的药理作用；2)研究RTLS对 免疫突触形成及RTL间结合作用的定量研究 和使用表面等离子体共振(Biacore)的TCR；以及3)表征 RTLS影响信号转导和T细胞的分子机制(S) 激活，以定义RTL治疗的时间框架和上下文 以抗原特异性的方式改变效应细胞。完成本建议书 将确定控制T细胞的独特干预点，进而 T细胞免疫反应和谱系。了解这些独特的、 合理设计的药物工作将为 CD4+T细胞介导的自身免疫性疾病的药物干预