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bioRxiv · 10.1101/2024.08.26.609625

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.
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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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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.. 2024-08-26. Comparative analysis of trans-chromosomic rodent models reveals improved somatic hypermutation and class-switch recombination in rats. https://doi.org/10.1101/2024.08.26.609625

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