Development of functional human blood and immune systems in NOD/SCID/IL2 receptor {gamma} chain(null) mice.
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/IL2rgamma(null) newborns via a facial vein. In all recipients injected with 10(5) hCD34(+) or 2 x 10(4) 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/IL2rgamma(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/IL2rgamma(null) newborn system might be an important experimental model to study the human hemato-lymphoid system.
Ishikawa
Fumihiko
F
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 44 Binney St, no. 770, Boston, MA 02115, USA.
Yasukawa
Masaki
M
Lyons
Bonnie
B
Yoshida
Shuro
S
Miyamoto
Toshihiro
T
Yoshimoto
Goichi
G
Watanabe
Takeshi
T
Akashi
Koichi
K
Shultz
Leonard D
LD
Harada
Mine
M
D036541:ADP-ribosyl Cyclase / Q000276:immunology; D051997:ADP-ribosyl Cyclase 1; D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D018952:Antigens, CD34 / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D036101:Cord Blood Stem Cell Transplantation; D004195:Disease Models, Animal; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007107:Immune System / Q000276:immunology*; D007231:Infant, Newborn; D008562:Membrane Glycoproteins; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D015375:Receptors, Interleukin-2 / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D014183:Transplantation, Heterologous / Q000276:immunology
D015703:Antigens, CD; D018952:Antigens, CD34; D008562:Membrane Glycoproteins; D015375:Receptors, Interleukin-2; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1