Generation of immunodeficient rats with Rag1 and Il2rg gene deletions and human tissue grafting models

Background Immunodeficient mice are invaluable tools to analyze the long-term effects of potentially immunogenic molecules in the absence of adaptive immune responses. Nevertheless, there are models and experimental situations that would beneficiate of larger immunodeficient recipients. Rats are ideally suited to perform experiments in which larger size is needed and are still a small animal model suitable for rodent facilities. Additionally, rats reproduce certain human diseases better than mice, such as ankylosing spondylitis and Duchenne disease and these disease models would greatly benefit of immunodeficient rats to test different immunogenic treatments. Methods We describe the generation of Il2rg-deficient rats and their crossing with previously described Rag1-deficient rats to generate double-mutant RRG animals. Results As compared to Rag1-deficient rats, Il2rg-deficient rats were more immunodeficient since partially lacked not only T and B cells but also NK cells. RRG animals showed a more profound immunossuppressed phenotype since they displayed undetectable levels of T, B and NK cells. Similarly, all immunoglobulin isotypes in sera were decreased in Rag1 or Il2rg-deficient rats and undetectable in RRG animals. Rag1 or Il2rg-deficient rats rejected allogeneic skin transplants and human tumors whereas RRG animals not only accepted allogeneic rat skin but also xenogeneic human tumors, skin and hepatocytes. Immune humanization of RRG animals was unsuccessful. Conclusion Thus, immunodeficient RRG animals are useful recipients for long term studies in which immune responses could be an obstacle, including tissue humanization of different tissues. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. * corresponding authors : severine.menoret@univ-nantes.fr and ianegon@nantes.inserm.fr. Disclosure: The authors declare no conflicts of interest. Authorship page Séverine Ménoret : Participated in research design, in the writing of the paper, in the performance of the research and in data analysis Laure-Hélène Ouisse: Participated in research design, in the writing of the paper, in the performance of the research and in data analysis Laurent Tesson: Participated in research design, in the performance of the research and in data analysis Frédéric Delbos: Participated in the writing of the paper, in the performance of the research and in data analysis Delphine Garnier: Participated in the performance of the research Séverine Remy: Participated in the performance of the research Claire Usal: Participated in the performance of the research Jean-Paul Concordet: Participated in research design, in the writing of the paper Carine Giovannangeli: Participated in research design, in the writing of the paperVanessa Chenouard; Participated in the performance of the research Lucas Brusselle: Participated in the performance of the research Emmanuel Merieau: Participated in the performance of the research Véronique Nerrière-Daguin : Participated in research design Franck Duteille: Contributed new reagents or analytic tools Frédérique Bellier-Waast: Contributed new reagents or analytic tools Alexandre Fraichard: Participated in research design Tuan H. Nguyen: Participated in research design, in the writing of the paper and in data analysis Ignacio Anegon: Participated in research design, in the writing of the paper, and in data analysis Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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