GENE TARGETED MICE WITH A SIMPLIFIED IMMUNE SYSTEM

描述（改编自研究者摘要）：基因靶向小鼠 简化的免疫系统。 即使在近交系中， 对简单抗原的免疫应答的可变区多样性 非常地。 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 抗体产生的问题可以用一种简单的 免疫系统，即，B细胞的基因只编码 一个或几个特征。 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， 对同源抗原免疫应答。 QM小鼠是一种基因靶向小鼠 在免疫球蛋白上重排的VDJ片段是纯合的， 重链基因座，另一个等位基因是非功能性的。 鼠标也 没有功能性κ轻链等位基因。 当重链配对时， 具有任何λ轻链，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QM小鼠将被 通过育种产生：（I）VDJ重链纯合小鼠 （ii）具有一个转基因VDJ等位基因和一个转基因VDJ等位基因的杂合小鼠; 种系构型中的正常重链基因座;（iii）QM和 具有重排的λ转基因的杂合小鼠;和（iv）具有 V（D）J重组酶阴性的重排λ转基因。 的 B细胞中等位基因排斥的程度和血清 QM小鼠中的免疫球蛋白以及来自它的QM衍生物将被 免疫前和免疫后的比较，有和没有过继转移。 此外，RAG和T细胞的独立机制的剧目， 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被沿着 非自我，这将导致自身免疫，或细胞显示两个 受体可能会从功能库中取出， 可用于预防疾病的所有功能。

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.