Human Hemato-Lymphoid System Mice: Current Use and Future Potential for Medicine

Abstract

To directly study complex human hemato-lymphoid system physiology and respective system-associated diseases in vivo, human-to-mouse xenotransplantation models for human blood and blood-forming cells and organs have been developed over the past three decades. We here review the fundamental requirements and the remarkable progress made over the past few years in improving these systems, the current major achievements reached by use of these models, and the future challenges to more closely model and study human health and disease and to achieve predictive preclinical testing of both prevention measures and potential new therapies.

Chemokine receptor engineering of T cells with CXCR2 improves homing towards subcutaneous human melanomas in xenograft mouse model

“…17 , 36 Our xenograft model relies on stromal chemokines secreted by mouse endothelial cells and fibroblasts, and despite some sequence similarity and evolutionary conserved regions, there is a greater disparity, and these may not necessarily support T cell adhesion, extravasation and tumor infiltration. 37 In line with this, HEVs in human melanoma lesions have been shown to be major gateways for tumor infiltrating lymphocytes, 38 however lack of host immune cells in the NOG mouse model, and thus no orchestrating chemokines and cytokines, HEVs are most likely not produced in this model. One could thus speculate that human-specific adhesion molecules may need to be expressed for optimal human immune cell migration and structural organization in the mouse model.…”

Animal models of Epstein Barr virus infection

“…The engraftment and maintenance of the human compartment could be improved by the genetic introduction of key human chemokines and cytokines that promote different cell types, as has been demonstrated for myeloid cell differentiation where the knock-in expression of human TPO, GM-CSF, and IL-3 resulted in improved myeloid populations (Willinger et al, 2011;Rongvaux et al, 2013). Animals expressing multiple human HLA transgenes would provide more complete Chatterjee et al 16 thymic T cell education and likely result in improved specific immune responses, as has been demonstrated in the HLA-A2 transgenic huNSG animals infected with EBV (Strowig et al, 2009).…”

“…These are generated using mouse strains with genetic lesions that compromise the development of mouse lymphocytes (Leung et al, 2013a;Rongvaux et al, 2013). Most commonly the non-obese diabetic (NOD) or the BALB/c mouse strain with scid or RAG mutations are used.…”

Insufficient interleukin‐12 signalling favours differentiation of human CD4+ and CD8+ T cells into GATA‐3+ and GATA‐3+ T‐bet+ subsets in humanized mice

“…9e) effector-like phenotype even in humanized mice that were not previous exposed to foreign antigen. 18 This T-cell activation is probably the result of increased homeostatic proliferation and/or recognition of mouse antigens by human T cells. However, the human T-cell population in HIS mice displays a broad T-cell receptor repertoire 27,39 indicating a polyclonal T-cell activation and not the expansion of specific T-cell clones.…”