GENE TARGETED MICE WITH A SIMPLIFIED IMMUNE SYSTEM

具有简化免疫系统的基因靶向小鼠

• 批准号: 6373658
• 负责人: MATTHIAS R WABL
• 金额: $ 25.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6373658
• 关键词: B cell receptor; B lymphocyte; animal breeding; antibody formation; gene expression; gene rearrangement; gene targeting; genetically modified animals; helper T lymphocyte; immunoglobulin genes; immunologic memory; laboratory mouse; tissue /cell culture

DESCRIPTION (Adapted from the Investigator's abstract): Gene-targeted mice with a simplified immune system. Even in inbred strains, the magnitude and variable region diversity of an immune response to a simple antigen varies enormously. This fact has hampered the precise prediction of the outcome of an immune response a major challenge for vaccine development. Many questions of antibody production can be attacked in mice with a simplified immune system, i.e., with B-cells that start out with genes encoding only one or a few specificities. The quasi-monoclonal (QM) mouse and its derivatives will be used to study the mechanism of allelic exclusion, generation of antibody diversity, serum immunoglobulin production, and the immune response to cognate antigen. The QM mouse is a gene-targeted mouse that is homozygous for a rearranged VDJ segment at the immunoglobulin heavy-chain locus, the other allele being non-functional. The mouse also has no functional kappa light chain allele. The heavy chain, when paired with any lambda light chain, is specific for the hapten NP. Derivatives of the QM mouse, with a variety of hemizygous and homozygous genotypes will be generated by breeding: (I) mice homozygous for the VDJ heavy -chain transgene; (ii) heterozygous mice with one transgenic VDJ allele and one normal heavy-chain locus in the germline configuration; (iii) QM and heterozygous mice with a rearranged lambda transgene; and (iv) QM mice with a rearranged lambda transgene that are V(D)J recombinase-negative. The degree of allelic exclusion in B-cells and the level of serum immunoglobulins in QM mice as well as the QM-derivatives from it will be compared before and after immunization, with and without adoptive transfer. Furthermore, RAG and T-cell independent mechanisms of repertoire diversifications will be studied. In the absence of allelic exclusion, receptors to self-antigens might be triggered along with receptors to non-self, which would lead to autoimmunity, or cells displaying two receptors might be taken out of the functional pool, which would diminish the repertoire available for protection against disease.

描述（改编自调查员的摘要）：靶向基因的小鼠 具有简化的免疫系统。 即使在近交菌株中，大小和 免疫反应对简单抗原的可变区域多样性各不相同 巨大。 这一事实阻碍了对结果的确切预测 免疫反应是疫苗开发的主要挑战。 许多 用简化的小鼠可以攻击抗体产生问题 免疫系统，即，B细胞仅以编码为基因的B细胞 一个或几个特殊性。 准单克（QM）鼠标及其 衍生物将用于研究等位基因排除的机制， 产生抗体多样性，血清免疫球蛋白产生和 对同源抗原的免疫反应。 QM鼠标是一种基因靶向的鼠标 对于免疫球蛋白的重新排列的VDJ段来说，这是纯合的 重链基因座，另一个等位基因非功能。 也是鼠标 没有功能性的Kappa轻链等位基因。 重链时，配对时 使用任何Lambda轻链，特定于Hapten NP。 衍生物 QM小鼠，具有多种半合子和纯合基因型的QM小鼠将是 由育种产生：（i）VDJ重链纯合子的小鼠 转基因； （ii）一只转基因VDJ等位基因和一只杂合小鼠 种系构型中的正常重链基因座； （iii）QM和 杂合小鼠，带有重新排列的lambda transgene； （iv）QM小鼠 一个重新排列的lambda转基因，即V（d）J重组酶阴性。 这 B细胞中的等位基因排除程度和血清水平 QM小鼠中的免疫球蛋白以及其QM衍生物将是 在免疫之前和之后进行了比较，有或没有收养转移。 此外，曲目和T细胞独立机制 将研究多样化。 在没有等位基因排除的情况下， 可能会触发自我抗原的受体，并与受体一起触发 非自身，这将导致自身免疫性或显示两个的单元格 受体可能会从功能库中取出，这会减少 曲目可用于保护疾病。