Differential Secondary Reconstitution ofIn Vivo-Selected Human SCID-Repopulating Cells in NOD/SCID versus NOD/SCID/γchainnullMice

摘要

Humanized bone-marrow xenograft models that can monitor the long-term impact of gene-therapy strategies will help facilitate evaluation of clinical utility. The ability of the murine bone-marrow microenvironment in NOD/SCID versus NOD/SCID/γchainnullmice to support long-term engraftment of MGMTP140K-transduced human-hematopoietic cells following alkylator-mediatedin vivoselection was investigated. Mice were transplanted with MGMTP140K-transduced CD34+cells and transduced cells selectedin vivo. At 4 months after transplantation, levels of human-cell engraftment, and MGMTP140K-transduced cells in the bone marrow of NOD/SCID versus NSG mice varied slightly in vehicle- and drug-treated mice. In secondary transplants, although equal numbers of MGMTP140K-transduced human cells were transplanted, engraftment was significantly higher in NOD/SCID/γchainnullmice compared to NOD/SCID mice at 2 months after transplantation. These data indicate that reconstitution of NOD/SCID/γchainnullmice with human-hematopoietic cells represents a more promising model in which to test for genotoxicity and efficacy of strategies that focus on manipulation of long-term repopulating cells of human origin.