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（改编自研究者的摘要）：基因靶向小鼠 具有简化的免疫系统。 即使在近交系中，其大小和 对简单抗原的免疫反应的可变区多样性有所不同 极大地。 这一事实妨碍了对结果的准确预测。 免疫反应是疫苗开发的主要挑战。 许多 可以通过简化的方法在小鼠中解决抗体产生的问题 免疫系统，即 B 细胞一开始只编码基因 一个或几个特殊性。 准单克隆（QM）小鼠及其 衍生物将用于研究等位基因排斥的机制， 抗体多样性的产生、血清免疫球蛋白的产生以及 对同源抗原的免疫反应。 QM小鼠是一种基因靶向小鼠 免疫球蛋白上重排的 VDJ 片段是纯合的 重链基因座，另一个等位基因无功能。 鼠标也 没有功能性 kappa 轻链等位基因。 配对时的重链 与任何 lambda 轻链一起，对半抗原 NP 具有特异性。 的衍生物 具有多种半合子和纯合子基因型的 QM 小鼠将 通过繁殖产生：（I）VDJ重链纯合的小鼠 转基因； (ii) 具有一个转基因VDJ等位基因和一个 种系构型中的正常重链位点； (iii) 质量管理和 带有重排的 lambda 转基因的杂合小鼠； (iv) QM 小鼠 V(D)J 重组酶阴性的重排 lambda 转基因。 这 B 细胞等位基因排除程度和血清水平 QM 小鼠中的免疫球蛋白及其 QM 衍生物将 比较免疫前后、有或没有过继转移的情况。 此外，RAG 和 T 细胞独立的机制 将研究多元化。 在没有等位基因排除的情况下， 自身抗原的受体可能会与自身抗原的受体一起被触发 非自身，这会导致自身免疫，或细胞显示出两种 受体可能会从功能池中取出，这会减少 可用于预防疾病的全部内容。