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 Blood, 1 September 2005, Vol. 106, No. 5, pp. 1565-1573.
Prepublished online as a Blood First Edition Paper on May 26, 2005; DOI 10.1182/blood-2005-02-0516.

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HEMATOPOIESIS

Development of functional human blood and immune systems in NOD/SCID/IL2 receptor {gamma} chainnull mice

Fumihiko Ishikawa, Masaki Yasukawa, Bonnie Lyons, Shuro Yoshida, Toshihiro Miyamoto, Goichi Yoshimoto, Takeshi Watanabe, Koichi Akashi, Leonard D. Shultz, and Mine Harada

From the Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; First Department of Internal Medicine, Ehime University School of Medicine, Shigenobu, Japan; The Jackson Laboratory, Bar Harbor, ME; Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan; RIKEN for Allergy and Immunology, Yokohama, Japan; and the Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA.

Here we report that a new nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse line harboring a complete null mutation of the common cytokine receptor {gamma} chain (NOD/SCID/interleukin 2 receptor [IL2r] {gamma}null) efficiently supports development of functional human hemato-lymphopoiesis. Purified human (h) CD34+ or hCD34+hCD38– cord blood (CB) cells were transplanted into NOD/SCID/IL2r{gamma}null newborns via a facial vein. In all recipients injected with 105 hCD34+ or 2 x 104 hCD34+hCD38– CB cells, human hematopoietic cells were reconstituted at approximately 70% of chimerisms. A high percentage of the human hematopoietic cell chimerism persisted for more than 24 weeks after transplantation, and hCD34+ bone marrow grafts of primary recipients could reconstitute hematopoiesis in secondary NOD/SCID/IL2r{gamma}null recipients, suggesting that this system can support self-renewal of human hematopoietic stem cells. hCD34+hCD38– CB cells differentiated into mature blood cells, including myelomonocytes, dendritic cells, erythrocytes, platelets, and lymphocytes. Differentiation into each lineage occurred via developmental intermediates such as common lymphoid progenitors and common myeloid progenitors, recapitulating the steady-state human hematopoiesis. B cells underwent normal class switching, and produced antigen-specific immunoglobulins (Igs). T cells displayed the human leukocyte antigen (HLA)–dependent cytotoxic function. Furthermore, human IgA-secreting B cells were found in the intestinal mucosa, suggesting reconstitution of human mucosal immunity. Thus, the NOD/SCID/IL2r{gamma}null newborn system might be an important experimental model to study the human hemato-lymphoid system.


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