Generation and Characterization of Severe Combined Immunodeficiency Rats

• Published in: Cell reports (Cambridge) Vol. 2; no. 3; pp. 685 - 694
• Main Authors: Mashimo, Tomoji, Takizawa, Akiko, Kobayashi, Junya, Kunihiro, Yayoi, Yoshimi, Kazuto, Ishida, Saeko, Tanabe, Koji, Yanagi, Ami, Tachibana, Asato, Hirose, Jun, Yomoda, Jun-ichiro, Morimoto, Shiho, Kuramoto, Takashi, Voigt, Birger, Watanabe, Takeshi, Hiai, Hiroshi, Tateno, Chise, Komatsu, Kenshi, Serikawa, Tadao
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.09.2012; Elsevier
• Subjects: Animals; Disease Models, Animal; DNA-Activated Protein Kinase - genetics; DNA-Activated Protein Kinase - metabolism; Gene Knockout Techniques; Humans; Interleukin Receptor Common gamma Subunit - genetics; Interleukin Receptor Common gamma Subunit - metabolism; Mice; Mice, SCID; Pluripotent Stem Cells - metabolism; Pluripotent Stem Cells - transplantation; Rats; Rats, Mutant Strains; Severe Combined Immunodeficiency; Transplantation, Heterologous
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2012.08.009

Severe combined immunodeficiency (SCID) mice, the most widely used animal model of DNA-PKcs (Prkdc) deficiency, have contributed enormously to our understanding of immunodeficiency, lymphocyte development, and DNA-repair mechanisms, and they are ideal hosts for allogeneic and xenogeneic tissue transplantation. Here, we use zinc-finger nucleases to generate rats that lack either the Prkdc gene (SCID) or the Prkdc and Il2rg genes (referred to as F344-scid gamma [FSG] rats). SCID rats show several phenotypic differences from SCID mice, including growth retardation, premature senescence, and a more severe immunodeficiency without “leaky” phenotypes. Double-knockout FSG rats show an even more immunocompromised phenotype, such as the abolishment of natural killer cells. Finally, xenotransplantation of human induced pluripotent stem cells, ovarian cancer cells, and hepatocytes shows that SCID and FSG rats can act as hosts for xenogeneic tissue grafts and stem cell transplantation and may be useful for preclinical testing of new drugs. [Display omitted] ► SCID rats were generated by zinc-finger nuclease technology ► SCID rats show growth retardation and severe immunodeficiency without leakiness ► Prkdc- and Il2rg-deficient rats are immunocompromised without NK cell activity ► SCID rats can be hosts for xenotransplantation of human stem cells and tissues Severe combined immunodeficiency (SCID) mice are the most widely used animal model in biologic and clinical sciences. They have contributed enormously to our understanding of the mechanisms underlying immunodeficiency and DNA repair and are ideal hosts for allogeneic and xenogeneic tissue transplantation. Mashimo and colleagues report the genetic engineering and characterization of major immunological properties of the first SCID rats. Because rats are ten times larger than mice, they are more suitable as a model for physiological, pharmacological, toxicological, and transplantation studies.