Comparative analysis of trans-chromosomic rodent models reveals improved somatic hypermutation and class-switch recombination in rats
Satofuka, H.; Abe, S.; Moriwaki, T.; Okada, A.; Kazuki, K.; Hamamichi, S.; Hiratsuka, M.; Hirabayashi, M.; Nakamura, K.; Sakuma, T.; Yamamoto, T.; Baba, Y.; Tomizuka, K.; Kazuki, Y.
Show abstract
Humanized rodent models, especially humanization of genetic/genomic components involved in immunity have significantly advanced our understanding of human immune system. Here, we utilized trans-chromosomic (Tc) technology to generate a TC-mAb rat model that stably harbors a mouse artificial chromosome carrying full-length human immunoglobulin (Ig) heavy and kappa light chain genes (IGHK-NAC) in a rat Ig knockout background. In contrast with TC-mAb mice, serum human IgG concentration was found higher than IgM. Number of lymphocytes was recovered, and B cell population in the spleen was normal. Remarkably, repertoire analysis revealed similarities between the model and human PBMCs; somatic hypermutation and class-switch recombination also more closely resembled humans. Furthermore, immunization resulted in generation of antigen-specific human antibodies. Collectively, our strategy to generate both rat and mouse models through introduction of the identical IGHK-NAC offers unprecedented opportunities to comprehensively evaluate genomic regulation and its outcomes associated with genomic sequences and host-derived protein factors.
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