GENE TARGETED MICE WITH A SIMPLIFIED IMMUNE SYSTEM

即使在近交系中，免疫的大小和V区多样性 对一种简单的抗原的反应差别很大。这一事实阻碍了 准确预测免疫反应的结果--这是一项重要的 疫苗开发面临的挑战。 许多抗体产生的问题都可以在患有AFP的小鼠身上解决 简化的免疫系统，即从基因开始的B细胞 只对一个或几个特性进行编码。准单克隆(QM)小鼠 并利用其衍生物研究等位基因的作用机制。 排异、血清免疫球蛋白的产生和对 同源抗原。QM小鼠是一种基因靶向的半合子小鼠 对于免疫球蛋白重链基因上重排的VDJ片段， 其他等位基因不起作用。鼠标也没有工作正常的kappa 轻链等位基因。重链，当与任何轻量的羔羊配对时 链，是半抗原NP所特有的。 QM小鼠的衍生品，具有多种半合子和纯合子 将通过繁殖产生以下基因类型：(I)VDJ纯合子小鼠 重链转基因，(Ii)VDJ转基因纯合子小鼠，但 CMU等位基因的杂合子，(Iii)一只转基因杂合子小鼠 VDJ等位基因和一个正常的重链基因座在生殖系结构中， (Iv)具有重排的lambda转基因的QM小鼠，以及(Vi) “超级小鼠”，对B细胞和辅助T细胞都是克隆的。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 未免疫前后、有无领养的比较 调职。 在没有等位基因排斥的情况下，自身抗原的受体可能是 与受体一起被触发到非我，这将导致 自身免疫，或显示两个受体的细胞可能会从 功能池，这将减少可用于 对疾病的保护。

Even in inbred strains, the magnitude and V 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, serum immunoglobulin production, and the immune response to cognate antigen. The QM mouse is a gene-targeted mouse that is hemizygous 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) mice homozygous for the VDJ transgene, but heterozygous for Cmu alleles, (iii) heterozygous mice with one transgenic VDJ allele and one normal heavy-chain locus in the germline configuration, (iv) QM mice with a rearranged lambda transgene, and (vi) the "supermouse", which is monoclonal for both B and helper T cells. 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 un-immunization, with and without adoptive transfer. 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.