Lonberg N, Huszar D
GenPharm International Inc., Mountain View, CA 94043, USA.
Int Rev Immunol. 1995;13(1):65-93. doi: 10.3109/08830189509061738.
We have used homologous recombination in ES cells to engineer B cell-deficient mice that are incapable of expressing endogenous immunoglobulin heavy and kappa light chain genes. We find that B cell development in these mutant mice can be rescued by the introduction of human germline-configuration heavy- and kappa light-chain minilocus transgenes. The transgenes rearrange during B cell differentiation, and subsequently undergo class switching and somatic mutation in response to antigen stimulation; thus recapitulating both stages of the humoral immune response using human, rather than mouse, sequences. The mice can be immunized; and human sequence, antigen specific, monoclonal antibodies can be obtained using conventional rodent hybridoma technology. These animals are also of interest for studying the normal processes of immunoglobulin gene expression. We discuss the example of heavy chain class switching, which has not been previously observed within an autonomous transgene.
我们利用胚胎干细胞中的同源重组技术构建了B细胞缺陷小鼠，这些小鼠无法表达内源性免疫球蛋白重链和κ轻链基因。我们发现，通过导入人胚系构型的重链和κ轻链微基因座转基因，可以挽救这些突变小鼠中的B细胞发育。转基因在B细胞分化过程中发生重排，随后在抗原刺激下进行类别转换和体细胞突变；从而利用人类而非小鼠序列重现体液免疫反应的两个阶段。这些小鼠可以进行免疫；并且可以使用传统的啮齿动物杂交瘤技术获得人源序列、抗原特异性的单克隆抗体。这些动物对于研究免疫球蛋白基因表达的正常过程也具有重要意义。我们讨论了重链类别转换的例子，这在自主转基因中以前尚未观察到。
