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 um bilical cord blood, bone marrow, or mobilized peripheral blood cells could be useful for the treatment of genetic and acquired disorders of the hemato poietic system, Immunodeficient mouse models have been used frequently as r ecipients to assay the growth and differentiation of human hematopoietic st em/progenitor cells. Indeed, high levels of human cell engraftment were fir st reported in human/murine chimeras using NOD/SCID mice, which now are con sidered as the standard for these types of experiments. However, NOD/SCID m ice have some clear disadvantages (including spontaneous tumor formation) t hat 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 tum or formation, and exhibit normal hematopoietic parameters. Interestingly, h uman cord blood cell engraftment in RAG2(-/-)/gamma c(-) mice was greatly e nhanced by the exogenous administration of human cytokines interleukin-(IL- 3) granulocyte-macrophage colony-stimulating factor, (GM-CSF), and erythrop oietin 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.