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(改编自研究人员摘要)：基因靶向小鼠 有一个简化的免疫系统。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各不相同 非常大。这一事实阻碍了对...结果的准确预测 免疫反应是疫苗开发的主要挑战.许多 小鼠的抗体产生问题可以用简化的 免疫系统，即B细胞开始时只编码基因 一个或几个细节。准单克隆化(QM)小鼠及其功能 将利用导数来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和 对同源抗原的免疫反应。QM小鼠是一种基因靶向的小鼠 这对于免疫球蛋白上重排的VDJ片段来说是纯合子的 重链基因，另一个等位基因是非功能性的。鼠标也是 没有功能性的kappa轻链等位基因。当配对时，沉重的链条 与任何波长轻链一起，都是半抗原NP所特有的。衍生品 QM小鼠，具有多种半合子和纯合子基因将是 繁殖产生的：(I)VDJ重链纯合子小鼠 转基因；(Ii)具有一个转基因VDJ等位基因和一个转基因VDJ等位基因的杂合子小鼠 胚系构型中的正常重链基因；(Iii)QM和 具有重排的lambda转基因的杂合子小鼠；和(Iv)具有 V(D)J重组酶阴性的重排的lambda转基因。这个 B细胞等位基因排斥程度与血清水平的关系 QM小鼠中的免疫球蛋白及其QM衍生物将被 比较免疫前后、有无收养转移的情况。 此外，RAG和T细胞的非依赖机制的谱系 将对多样化进行研究。在没有等位基因排斥的情况下， 自身抗原的受体可能与受体一起被触发 非我，这会导致自身免疫，或者细胞显示两个 受体可能会被从功能池中移除，这将减少 可用于预防疾病的曲目。