One mechanism by which irradiation is thought to enhance HSC engraftment is by stimulating the release of factors that improve the homing and survival of stem cells such as stem cell factor (SCF) [63] and SDF-1 [68]. However, total body irradiation has a number of negative consequences, including stunting growth and impairing neuronal function [19, 69]. Recent work from our laboratory and others have demonstrated that both adult and newborn selleck compound NSG mice will support human

HSC engraftment in the absence of irradiation [69, 70]. Moreover, the transgenic expression of human SCF improves human HSC engraftment significantly in non-irradiated NSG mice [69]. In this study we show that irradiation is not essential for the human immune system development in NSG–BLT mice, although irradiation increases levels of human chimerism. One significant difference for non-irradiated NSG–BLT Dorsomorphin mice

was the lower level of human IgM detected in the serum compared to NSG–BLT mice that were preconditioned with irradiation. The reduced levels of IgM may be attributed to the slightly reduced levels of human B cells in the spleens of non-irradiated NSG–BLT mice. To allow for complete analysis of the engraftment data, we have also presented the human cell chimerism levels shown in Figs 1-3 (human CD45+, human CD3+ T cells and human CD20+ B cells) for each unique set of human fetal tissues (Supporting information, Fig. S9). The NSG–BLT mouse has sustained high levels

of human cell chimerism and T cells in the peripheral lymphoid tissues. However, many NSG–BLT mice succumb ultimately to a GVHD-like syndrome [54] which has also been reported for BLT mice generated on the NOD-scid background [26]. The development of the delayed GVHD-like syndrome in NSG–BLT mice correlated with the transition of human T cells to an activated phenotype and increased G protein-coupled receptor kinase levels of human IgM and IgG in the serum. This late, spontaneous activation of the human immune systems suggests that a peripheral tolerance mechanism is abrogated as NSG–BLT mice age, and this loss of tolerance allows the human immune system to respond to the murine host. T cells are a primary effector population mediating tissue damage during classic GVHD [71], and the high levels of human T cell chimerism in the NSG–BLT mice suggest that these cells are key mediators of the disease pathology. Our data show that the development of GVHD in NSG–BLT mice does not require the expression of murine MHC classes I or II, indicating that either human CD4 or CD8 T cells or both probably mediate GVHD, or that murine MHC classes I or II are not necessary for disease development. We are initiating studies to evaluate further the mechanism mediating GVHD in NSG–BLT mice by generating NSG mice that lack both murine classes I and II and by the depletion of human T cell subsets at precise time-points.