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null Mice Engrafted with Mobilized Human Hemopoietic Stem Cells 1,2
* The Jackson Laboratory, Bar Harbor, ME 04609; St. Jude Children’s Research Hospital, Memphis, TN 38105; University of Tennessee Health Sciences Center, Memphis, TN 38163; EMD Lexigen Research Center, Billerica, MA 01821; and ¶ University of Massachusetts Medical School, Worcester, MA 01655
Ethical considerations constrain the in vivo study of human hemopoietic stem cells (HSC). To overcome this limitation, small animal models of human HSC engraftment have been used. We report the development and characterization of a new genetic stock of IL-2R common 
-chain deficient NOD/LtSz-scid (NOD-scid IL2Rnull) mice and document their ability to support human mobilized blood HSC engraftment and multilineage differentiation. NOD-scid IL2Rnull mice are deficient in mature lymphocytes and NK cells, survive beyond 16 mo of age, and even after sublethal irradiation resist lymphoma development. Engraftment of NOD-scid IL2Rnull mice with human HSC generate 6-fold higher percentages of human CD45+ cells in host bone marrow than with similarly treated NOD-scid mice. These human cells include B cells, NK cells, myeloid cells, plasmacytoid dendritic cells, and HSC. Spleens from engrafted NOD-scid IL2Rnull mice contain human Ig+ B cells and lower numbers of human CD3+ T cells. Coadministration of human Fc-IL7 fusion protein results in high percentages of human CD4+CD8+ thymocytes as well human CD4+CD8– and CD4–CD8+ peripheral blood and splenic T cells. De novo human T cell development in NOD-scid IL2Rnull mice was validated by 1) high levels of TCR excision circles, 2) complex TCR
repertoire diversity, and 3) proliferative responses to PHA and streptococcal superantigen, streptococcal pyrogenic exotoxin. Thus, NOD-scid IL2Rnull mice engrafted with human mobilized blood stem cells provide a new in vivo long-lived model of robust multilineage human HSC engraftment.
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