Humanized mice for the study of infectious diseases

Abstract

Many of the pathogens that cause human infectious diseases do not infect rodents or other mammalian species. Small animal models that allow studies of the pathogenesis of these agents and evaluation of drug efficacy are critical for identifying ways to prevent and treat human infectious diseases. Immunodeficient mice engrafted with functional human cells and tissues, termed 'humanized' mice, represent a critical pre-clinical bridge for in vivo studies of human pathogens. Recent advances in the development of humanized mice have allowed in vivo studies of multiple human infectious agents providing novel insights into their pathogenesis that was otherwise not possible.

Figure 1. Four major methods of engrafting NSG mice with human hematopoietic cells and tissues

NSG and other strains of immunodeficient mice have been engrafted with human hematopoietic and immune cells or tissues to establish four different immune system engraftment models Hu-PBL-SCID: This model is established by engraftment of human Peripheral Blood Leukocytes (PBL). Most of the engrafting cells are human T cells that express an activated phenotype while few B cells or myeloid cells engraft. This model, described in 1988 [10], is ideal for the study of agents that infect mature effector T cells such as HIV-1 [67]. 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 [68]. Hu-SRC-SCID: This model, termed the Human Stem Repopulating Cell model, 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 [69] while human T cells are readily generated following engraftment of newborn or 3-4 week-old NSG and NOG mice with HSC [15;69]. SCID-Hu: This model is established by implantation of human fetal liver and thymus fragments under the renal capsule of immunodeficient mice [14]. Although this was one of the first models available for the study of human immunodeficiency virus-1 (HIV-1), a major limitation is the paucity of human hematopoietic and immune cells in the peripheral tissues. BLT: This model (Bone marrow, Liver, Thymus) 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 [11]. Use of immunodeficient NOD-scid mice to establish the BLT model led to human immune system engrafted mice [70;71], which is further enhanced by the engraftment of NSG mice [27]. A complete hematopoietic and immune system develops, and the human T cells are educated on a human thymus and are HLA-restricted [19;20]. This model has become the model of choice for studies of many infectious agents due to the robust human immune system and the generation of a human mucosal immune system.