A New Model for Studying Antigen-driven B cell Tolerance

研究抗原驱动的 B 细胞耐受性的新模型

• 批准号: 7028267
• 负责人: TIMOTHY L MANSER
• 金额: $ 7.62万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-15 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7028267
• 关键词: B lymphocyte; anergy; apoptosis; autoantigens; autoimmunity; biological models; genetically modified animals; immune response genes; immune tolerance /unresponsiveness; immunoregulation; laboratory mouse; model design /development

DESCRIPTION (provided by applicant): The experiments described in this proposal were motivated by the results of ongoing work currently being funded by an R01. These ongoing studies are designed to provide insight into the manner in which B cells reactive with both foreign and autoantigens ("dual reactive" B cells) are regulated to prevent the induction of autoimmunity. As part of our long term commitment to these studies, we attempted to generate a new line of VH "knockin" mice, using a VH gene that partially encodes chromatin/arsonate "dual reactive" antibodies. We expected this venture to take several years and, as such, this was not discussed in the RO1. However, to our good fortune we succeeded on the first attempt. This new knockin line may provide us with the ability to conduct very high resolution experiments on the developmental fate of chromatin/arsonate B cells both prior to and during the immune response. Here, we propose to evaluate whether the progeny of "dual reactive" B cells clones are subjected to a peripheral tolerance "checkpoint" in the germinal center, and whether this checkpoint operates via clonal deletion, receptor editing, or regulation of V gene hypermutation.

描述（由申请人提供）：本提案中描述的实验是由目前由R01资助的正在进行的工作的结果激励的。这些正在进行的研究旨在洞悉B细胞用外抗原和自身抗原（“双重反应性” B细胞）反应性的方式，以防止诱导自身免疫性。作为我们对这些研究的长期承诺的一部分，我们尝试使用一种用VH基因部分编码染色质/纵火质“双反应性”抗体来生成新的VH“敲蛋白”小鼠系列。我们预计这项冒险将需要几年的时间，因此，RO1中没有讨论。但是，为了我们的好运，我们取得了首次尝试。这种新的敲蛋白线可以使我们能够在免疫反应之前和期间对染色质/纵火质B细胞的发育命运进行非常高的分辨率实验。在这里，我们建议评估“双重反应性” B细胞克隆的后代是否在生发中心遭受外周耐受性“检查点”，以及该检查点是否通过克隆缺失，受体编辑，受体编辑或V基因过度的调节进行操作。