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R 01资助的正在进行的工作的结果激发的。这些正在进行的研究旨在提供对B细胞与外源抗原和自身抗原反应（“双重反应”B细胞）的调节方式的了解，以防止诱导自身免疫。作为我们对这些研究的长期承诺的一部分，我们尝试使用部分编码染色质/胂酸盐“双重反应性”抗体的VH基因来产生新的VH“敲入”小鼠系。我们预计这一风险投资需要几年时间，因此，在RO 1中没有讨论这一问题。然而，我们运气好，第一次尝试就成功了。这一新的敲入系可能为我们提供了在免疫应答之前和期间对染色质/砷化物B细胞的发育命运进行非常高分辨率实验的能力。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受到外周耐受性“检查点”的影响，以及这个检查点是否通过克隆缺失、受体编辑或V基因超突变调控来发挥作用。