Core C-Antibody Core

核心 C-抗体核心

• 批准号: 8376125
• 负责人: Gordon James Freeman
• 金额: $ 32.42万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8376125
• 关键词: Agonist; Antibodies; Attenuated; Binding; CTLA4 gene; Cells; Chimeric Proteins; Chronic; Chronic Hepatitis C; Data; Failure; Generations; Goals; Hepatitis C; Hepatitis C virus; Immune; Immune response; In Vitro; Infection; Investigation; KLRB1 gene; Ligands; Lymphocytic choriomeningitis virus; Mission; Modeling; Monoclonal Antibodies; Pathway interactions; Production; Proteins; Reagent; Receptor Signaling; Regulatory Pathway; Research Personnel; Role; Signal Transduction; Standardization; T cell response; T-Cell Receptor; T-Lymphocyte; Testing; Time; Work; anti-hepatitis C; cost efficient; crosslink; exhaust; exhaustion; high throughput screening; member; novel; prototype; receptor; repository; small molecule; success; technology development

Coinhibitory signals attenuate T cell receptor signaling and inhibit T cell responses. PD-1 is the prototype coinhibitory receptor and has been shown to be highly expressed on exhausted hepatitis C virus (HCV)- specific T cells that have lost effector functions. Blockade of PD-1 with monoclonal antibodies (mAb) enhances HCV-specific CDS T cells responses in vitro. Our hypothesis is that coinhibitory pathways contribute to exhaustion of HCV-specific T cells, regulating progression to chronic infection, and that blockade of coinhibitory pathways will enhance effective anti-HCV immune responses. Recent work shows that additional coinhibitory pathways contribute to T cell exhaustion and that blockade of multiple coinhibitory pathways optimally enhances T cell responses. Core C will focus on the PD-1, CD160, LAG-3, CTLA4, and CD161 coinhibitory pathways identified by this work. Core C will generate and produce mAbs that will facilitate analysis of the function and expression of the PD-1/PD-1 Ligand pathway as well as other coinhibitory pathways including CD160, LAG-3, CTLA4, and CD161 pathways. Core C will generate novel dimeric and multimeric Ig fusion proteins of these coinhibitory pathway proteins in order to either block or transduce signals via cross-linking receptors. The capacity of these blocking mAbs to enhance HCV-specific T cell responses will be tested. These mAbs and Ig fusion proteins will be used in high throughput assays by Technology Development Project 1 to identify small molecule antagonists of coinhibitory pathways. Core C provides a critical means by which the U19 will achieve its goals of understanding how to manipulate the coinhibitory signals provided by PD-1, CD160, LAG-3, CTLA4, CD161 and their ligands as well as the mechanism of these inhibitory signals. Core C will work closely with project investigators, providing them mAbs and Ig fusion proteins as needed.

共抑制信号减弱T细胞受体信号传导并抑制T细胞应答。PD-1是原型 共抑制受体，并已被证明是高度表达的耗尽丙型肝炎病毒（HCV）- 失去效应子功能的特异性T细胞。用单克隆抗体（mAb）阻断PD-1 在体外增强HCV特异性CD 8 T细胞应答。我们的假设是共抑制通路 有助于HCV特异性T细胞的耗竭，调节慢性感染的进展， 共抑制途径的阻断将增强有效的抗HCV免疫应答。最近的工作表明 额外共抑制途径有助于T细胞耗竭和多种共抑制途径的阻断， 最佳途径增强T细胞应答。核心C将重点关注PD-1、CD 160、LAG-3、CTLA 4和 CD 161共抑制通路通过这项工作确定。核心C将生成并产生mAb， 有助于分析PD-1/PD-1配体途径以及其他 共抑制途径包括CD 160、LAG-3、CTLA 4和CD 161途径。核心C将产生新的 这些共抑制途径蛋白的二聚体和多聚体IG融合蛋白，以便阻断或 通过交联受体传递信号。这些阻断mAb增强HCV特异性免疫应答的能力， 将测试T细胞应答。这些mAb和IG融合蛋白将用于高通量测定， 技术开发项目1，用于鉴定共抑制途径的小分子拮抗剂。芯C 提供了一个关键的手段，U19将实现其目标，了解如何操纵 由PD-1、CD 160、LAG-3、CTLA 4、CD 161及其配体以及它们的配体提供的共抑制信号 这些抑制信号的机制。核心C将与项目调查人员密切合作，为他们提供 mAb和IG融合蛋白。