A Vh gene that blocks development of follicular B cells

阻碍滤泡 B 细胞发育的 Vh 基因

• 批准号: 7025800
• 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/7025800
• 关键词: B cell receptor; B lymphocyte; SCID mouse; bone marrow; developmental immunology; hematopoietic stem cells; hematopoietic tissue transplantation; immunoglobulin genes; immunoglobulin structure; laboratory mouse; lymphopenia; lymphopoiesis; stem cell transplantation

DESCRIPTION (provided by applicant): A VH gene that fails to promote development of follicular B cells. We have generated novel lines of mice by introducing the VH genes from 2 anti-arsonate hybridomas into a natural location in the endogenous Igh locus (VH "knockin" mice). 1 of these lines, called HKI65, contains a VH gene that lacks somatic mutations. This VH gene can alone promote normal development of B1, B2 and marginal zone (MZ) B cells, as shown when it is present in the context of an inactivated JH locus on the other allele (JHD). In striking contrast, in another VH knockin/JHD line (termed HKI71) in which the VH gene differs from that in the HKI65 line by only 8 amino acid substitutions, B2 cells are essentially absent, B1 cells are present at near normal levels in the peritoneum, and most B cells in the spleen are of the MZ phenotype. Preliminary analysis of adult bone marrow B cell development in HKI71mice indicates a severe block at or about the pre-B stage of development. Further studies of HKI71/JHD mice promise to provide new insights into the factors that regulate the development of MZ B cells. However, to allow such future studies to be clearly defined, more detailed preliminary data are required. In particular, the nature of the defect in B lymphopoiesis needs to be investigated. In addition, since MZ B cells are thought to have the ability to expand and self-renew in the periphery, whether the predominance of MZ B cells in HKI71/JHD mice results from events secondary to a state of B lymphopenia during the development of HKI71/JHD mice needs to be addressed. In this proposal, 2 focused specific aims are described that will address these issues.

描述（由申请人提供）：无法促进滤泡 B 细胞发育的 VH 基因。我们通过将来自 2 个抗胂酸杂交瘤的 VH 基因引入内源性 Igh 基因座的自然位置（VH“敲入”小鼠），产生了新的小鼠品系。其中 1 个品系称为 HKI65，含有缺乏体细胞突变的 VH 基因。该 VH 基因可以单独促进 B1、B2 和边缘区 (MZ) B 细胞的正常发育，如当它存在于另一个等位基因 (JHD) 上失活的 JH 基因座的背景下时所示。与此形成鲜明对比的是，在另一个 VH 敲入/JHD 系（称为 HKI71）中，其中 VH 基因与 HKI65 系中的 VH 基因仅存在 8 个氨基酸取代不同，B2 细胞基本上不存在，而 B1 细胞以接近正常水平存在。腹膜和脾脏中的大多数 B 细胞属于 MZ 表型。对 HKI71 小鼠中成人骨髓 B 细胞发育的初步分析表明，在前 B 阶段或大约发育阶段存在严重阻碍。对 HKI71/JHD 小鼠的进一步研究有望为调节 MZ B 细胞发育的因素提供新的见解。然而，为了明确定义此类未来的研究，需要更详细的初步数据。特别是，需要研究 B 淋巴细胞生成缺陷的性质。此外，由于MZ B细胞被认为具有在外周扩张和自我更新的能力，因此HKI71/JHD小鼠中MZ B细胞的优势是否是由HKI71发育过程中B淋巴细胞减少状态继发的事件导致的/JHD 小鼠需要解决。在此提案中，描述了解决这些问题的 2 个具体目标。