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: 6529778
• 负责人: GREGORY George BURROWS
• 金额: $ 33.44万
• 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/6529778
• 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（由研究者提供）：本研究的目标是 了解并控制致病性 T 细胞的激活。激活T 细胞是由抗原特异性 T 共连接引发的多步骤过程 细胞受体 (TCR) 和辅助受体 CD4 与 MHC II 类/肽复合物 存在于抗原呈递细胞 (APC) 上（信号 I），包括 通过 T 细胞表面分子（例如 CD28）进行共刺激（信号 2）。我们的 工作假设是 T 细胞可以通过调节环境来控制 其中 MHC/肽与 TCR 相互作用。 为了检验这个假设，我们最近开发了一系列小说 源自 HLADR2 α-1 和 β-1 结构域的重组 TCR 配体 (RTL)， 有或没有共价连接的肽抗原。 RTL 技术是 首次在多发性硬化症 EAE 动物模型中进行描述 （实验性自身免疫性脑脊髓炎）。 RTLs 抑制激活 致病性 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性疾病方面的潜力 疾病为开发人类 RTL 和进一步 表征分子调节 CD4+ 致病性 T 的机制 细胞。我们建议 1) 对人类 RTL 进行生化表征，以增强 分子的药理学用途； 2) 研究 RTL 对 免疫突触形成并定量 RTL 之间的结合相互作用 和使用表面等离子共振（Biacore）的TCR； 3) 表征 RTL 影响信号转导和 T 细胞的分子机制 激活，以定义 RTL 治疗可以进行的时间范围和背景 以抗原特异性方式改变效应细胞。完成本提案 将确定控制 T 细胞的独特干预点，进而 T 细胞免疫反应和指令集。了解这些独特之处， 合理的工程药物工作将为 CD4+ T 细胞介导的自身免疫性疾病的药物干预。