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: 6867838
• 负责人: TIMOTHY L MANSER
• 金额: $ 7.8万
• 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/6867838
• 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）：一种无法促进卵泡B细胞发展的VH基因。我们通过将来自2种抗艾尔森酸杂交瘤的VH基因引入内源性IGH基因座（VH“敲门蛋白”小鼠）的自然位置，从而产生了新的小鼠。其中1个称为HKI65，包含缺乏体细胞突变的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，如它在另一个等位基因（JHD）上灭活的JH基因座的背景下显示时所示。在引人注目的对比中，在另一条VH敲击蛋白/JHD系（称为HKI71）中，其中VH基因与HKI65系中仅通过8个氨基酸取代而不同，B2细胞基本上没有B2细胞，B1细胞存在于腹膜中的大多数B细胞，并且大多数B细胞中的大多数B细胞是MZ Permotype的spleen型。对HKI71MICE的成年骨髓B细胞发育的初步分析表明，在B前发育前或B之前存在严重的阻滞。 HKI71/JHD小鼠的进一步研究有望提供有关调节MZ B细胞发展的因素的新见解。但是，为了清楚地定义这样的未来研究，需要更详细的初步数据。特别是，需要研究B淋巴管中缺陷的性质。此外，由于MZ B细胞被认为具有在外围扩展和自我更新的能力，因此是否需要解决HKI71/JHD小鼠的发展中MZ B细胞在HKI71/JHD小鼠中的主要占主导地位。在此提案中，描述了2个重点的特定目标，可以解决这些问题。