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Prepublished online as a Blood First Edition Paper on July 5, 2002; DOI 10.1182/blood-2001-12-0207.
Submitted December 14, 2001
Accepted April 30, 2002
NOD/SCID/ cnull mouse: an excellent recipient mouse model for engraftment of human cells
Mamoru Ito*, Hidefumi Hiramatsu, Kimio Kobayashi, Kazutomo Suzue, Mariko Kawahata, Kyoji Hioki, Yoshito Ueyama, Yoshio Koyanagi, Kazuo Sugamura, Kohichiro Tsuji, Toshio Heike, and Tatsutoshi Nakahata
Central Institute for Experimental Animals, Kanagawa, Japan
Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Department of Parasitology, School of Medicine, Gunma University, Gunma, Japan
Department of Pathology, School of Medicine, Tokai University, Kanagawa, Japan
Department of Virology, Graduate School of Medicine, Tohoku University, Miyagi, Japan
Department of Immunology, Graduate School of Medicine, Tohoku University, Miyagi, Japan
Division of Cellular Therapy, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
* Corresponding author; email: mito{at}ciea.or.jp.
To establish a more appropriate animal recipient for xenotransplantation, NOD/SCID/cnull mice double homozygous for the severe combined immunodeficiency (SCID) mutation and IL-2R allelic mutation (cnull) were generated by 8 back-cross matings of C57BL/6J-cnull mice and NOD/Shi-scid mice. When human CD34+ cells from umbilical cord blood were transplanted into this strain, the engraftment rate in the peripheral circulation, spleen, and bone marrow were significantly higher than that in NOD/Shi-scid mice treated with anti-asialo GM1 antibody or in the ß2-microglobulin deficient NOD/LtSz-scid (NOD/SCID/ß2m null) mice, which were as completely defective in NK cell activity as NOD/SCID/cnull mice. The same high engraftment rate of human matured cells was observed in ascites when peripheral blood mononuclear cells were intraperitoneally transferred. In addition to the high engraftment rate, multi-lineage cell differentiation was also observed. Further, even 1 x 102 CD34+ cells could grow and differentiate in this strain. These results suggest that NOD/SCID/cnull mice were superior animal recipients for xenotransplantation, and especially valuable for human stem cell assay. To elucidate the mechanisms involved in the superior engraftment rate in NOD/SCID/cnull mice, cytokine production of spleen cells stimulated with Listeria monocytogenes antigens was compared among these three strains of mice. The IFN- production from dendritic cells from the NOD/SCID/cnull mouse spleen was significantly suppressed in comparison with findings in 2 other strains of mice. It is suggested that multiple immunological dysfunctions, including cytokine production capability, in addition to functional incompetence of T, B and NK cells, may lead to the high engraftment levels of xenografts in NOD/SCID/cnull mice.
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