A novel immunodeficient mouse model--RAG2 x common cytokine receptor gamma chain double mutants--requiring exogenous cytokine administration for human hematopoietic stem cell engraftment.
Gene transduction into immature human hematopoietic cells collected from umbilical cord blood, bone marrow, or mobilized peripheral blood cells could be useful for the treatment of genetic and acquired disorders of the hematopoietic system. Immunodeficient mouse models have been used frequently as recipients to assay the growth and differentiation of human hematopoietic stem/progenitor cells. Indeed, high levels of human cell engraftment were first reported in human/murine chimeras using NOD/SCID mice, which now are considered as the standard for these types of experiments. However, NOD/SCID mice have some clear disadvantages (including spontaneous tumor formation) that limit their general use. We have developed a new immunodeficient mouse model by combining recombinase activating gene-2 (RAG2) and common cytokine receptor gamma chain (gamma c) mutations. The RAG2-/-/gamma c- double mutant mice are completely alymphoid (T-, B-, NK-), show no spontaneous tumor formation, and exhibit normal hematopoietic parameters. Interestingly, human cord blood cell engraftment in RAG2-/-/gamma c- mice was greatly enhanced by the exogenous administration of human cytokines interleukin-(IL-3) granulocyte-macrophage colony-stimulating factor, (GM-CSF), and erythropoietin in contrast to the NOD/SCID model. This unique feature of the RAG2-/-/gamma c- mouse model should be particularly well suited for assessing the role of different cytokines in human lymphopoiesis and stem/progenitor cell function in vivo.
Mazurier
F
F
Laboratoire de Pathologie Moléculaire et Thérapie Génique, UMR CNRS 5540, Fédération de Recherche 60 Biologie des Greffes, Université Victor Segalen, Bordeaux, France.
Fontanellas
A
A
Salesse
S
S
Taine
L
L
Landriau
S
S
Moreau-Gaudry
F
F
Reiffers
J
J
Peault
B
B
Di Santo
J P
JP
de Verneuil
H
H
D000818:Animals; D018952:Antigens, CD34 / Q000097:blood; D016207:Cytokines / Q000494:pharmacology*; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D009687:Nuclear Proteins; D010446:Peptide Fragments / Q000235:genetics*; D010641:Phenotype; D018121:Receptors, Cytokine / Q000737:chemistry / Q000235:genetics*; D016511:Severe Combined Immunodeficiency / Q000235:genetics*
D018952:Antigens, CD34; D016207:Cytokines; D004268:DNA-Binding Proteins; D007377:Interleukin-3; D009687:Nuclear Proteins; D010446:Peptide Fragments; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; D018121:Receptors, Cytokine; C064655:V(D)J recombination activating protein 2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor