Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells.
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 gamma-chain deficient NOD/LtSz-scid (NOD-scid IL2Rgamma(null)) mice and document their ability to support human mobilized blood HSC engraftment and multilineage differentiation. NOD-scid IL2Rgamma(null) 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 IL2Rgamma(null) 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 IL2Rgamma(null) 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 IL2Rgamma(null) mice was validated by 1) high levels of TCR excision circles, 2) complex TCRbeta repertoire diversity, and 3) proliferative responses to PHA and streptococcal superantigen, streptococcal pyrogenic exotoxin. Thus, NOD-scid IL2Rgamma(null) mice engrafted with human mobilized blood stem cells provide a new in vivo long-lived model of robust multilineage human HSC engraftment.
Shultz
Leonard D
LD
The Jackson Laboratory, Bar Harbor, ME 04609, USA. lds@jax.orgn
Lyons
Bonnie L
BL
Burzenski
Lisa M
LM
Gott
Bruce
B
Chen
Xiaohua
X
Chaleff
Stanley
S
Kotb
Malak
M
Gillies
Stephen D
SD
King
Marie
M
Mangada
Julie
J
Greiner
Dale L
DL
Handgretinger
Rupert
R
D000375:Aging / Q000235:genetics / Q000276:immunology; D000818:Animals; D001772:Blood Cell Count; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D003713:Dendritic Cells / Q000166:cytology; D005260:Female; D005434:Flow Cytometry; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods; D006801:Humans; D007136:Immunoglobulins / Q000097:blood; D016130:Immunophenotyping; D053631:Interleukin Receptor Common gamma Subunit; D007694:Killer Cells, Natural / Q000276:immunology; D008136:Longevity / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D008223:Lymphoma / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D038041:Lymphopoiesis / Q000235:genetics* / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D038042:Myelopoiesis / Q000235:genetics* / Q000276:immunology*; D036102:Peripheral Blood Stem Cell Transplantation / Q000379:methods*; D011836:Radiation Tolerance / Q000235:genetics / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D020395:Receptors, Interleukin-7 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology
C507941:IL2RG protein, human; C507942:Il2rg protein, mouse; D007136:Immunoglobulins; D053631:Interleukin Receptor Common gamma Subunit; D015375:Receptors, Interleukin-2; D020395:Receptors, Interleukin-7