Fig. 3: Humanized mice models for the in vivo immunological assessment of cellular therapies.

Illustration representing the methodologies behind current humanized mice models highlighting the advantages (check) and disadvantages (cross) of each model. The models include: the human peripheral blood lymphocytes (Hu-PBL-SCID) in which most of the engrafting cells are human T cells that express an activated phenotype while few B cells or myeloid cells engraft. One caveat is that these mice will develop a xenogeneic graft-versus-host disease (xeno-GVHD) that results in death, but xeno-GVHD can be delayed using immunodeficient mice lacking mouse MHC class I or class II; the human stem cell repopulating cell (Hu-SRC-SCID), which is established by engraftment of human hematopoietic stem cells (HSC) derived from bone marrow, umbilical cord blood, fetal liver, or mobilized peripheral blood HSC. Engrafting mature adult immunodeficient IL2rγ null mice with HSC permits the generation of multiple hematopoietic cell lineages but few T cells while human T cells are readily generated following engraftment of newborn or 3–4 week-old NSG and NOG mice with HSC; the SCID-HU, which is established by implantation of human fetal liver and thymus fragments under the renal capsule of immunodeficient mice and a major limitation is the paucity of human hematopoietic and immune cells in the peripheral tissues; and the bone marrow, liver, thymus (BLT), which is established by implantation of human fetal liver and thymus fragments under the renal capsule of sublethally irradiated immunodeficient mice accompanied by intravenous injection of autologous fetal liver HSC. The use of immunodeficient NOD-scid mice to establish the BLT model led to human immune system engrafted mice, which is further enhanced by the engraftment of NSG mice. A complete hematopoietic and immune system develops, and the human T cells are educated on a human thymus and are HLA-restricted. IP: intraperitoneal, IV: intravenous, IS: intrasplenic, IF: intrafemoral, IC: intracardiac, IH: intrahepatic, GvHd: graft versus host disease.