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.

Figure 1

Utility of humanized mouse models for predictive in vivo preclinical testing of physiology, pathology, and therapy. With the generation of predictive humanized mouse model systems, knowledge of primary human-specific physiology and pathology can be accelerated and utilized for medical improvements.

Figure 2

Differences in the white blood cell composition and in the gut microbiota of human and mouse. (a) White blood cell differential of human and mouse. Whereas human blood is rich in myeloid cells (granulocytes and monocytes), the composition of mouse blood is dominated by lymphocytes (B and T cells). The functional and evolutionary significance of this difference is currently unknown. (b) Bacteroidetes and Firmicutes are the two most abundant phyla present in the gut microbiota of vertebrates. However, significant differences in bacterial species representation exist, depending on the species of the host. Operational taxonomic units (OTUs) shared between human and mouse ( green), specific for human (blue), and specific for mouse (red ) hosts are represented for each bacterial phylum. The host-specific microbiota is required for adequate maturation and function of the immune system. Data modified from Reference 207.

Figure 3

A nonexhaustive list of key factors required for hemato-lymphoid system development and maintenance. Only factors that are produced mostly by nonhematopoietic cells are depicted. The color code indicates the percentage of amino acid identity between the human and mouse proteins (see also Supplemental Table 1).

Figure 4

A nonexhaustive list of key factors required for the terminal differentiation, activation, and migration of hematopoietic cell lineages. Also shown are factors that mediate the effector functions of hematopoietic cells and act on nonhematopoietic tissues. The same color code as in Figure 3 is used (see also Supplemental Table 1).

Figure 5

Theoretical representation of human T cell selection and function in a mouse environment. (a) A functional T cell repertoire is selected in the thymus. Thymocytes first undergo positive selection (i.e., the survival of thymocytes expressing a T cell receptor that interacts with MHC, and death by neglect of those that do not interact) in the thymus cortex. This process is in physiology mediated by MHC-expressing epithelial cells of mouse origin. However, in HHLS mice, an alternative thymocyte-thymocyte selection pathway might be active for some human thymocytes (see text). Next, positively selected thymocytes undergo negative selection in the thymus medulla. This process consists of the elimination of T cells that bind to MHC/self-peptide complexes with high affinity, and it results in the establishment of central tolerance. Negative selection is mediated by mouse medullary epithelial cells and by dendritic cells that can be of mouse or human origin. (b) Once T cells are released from the thymus, their homeostatic maintenance in the periphery requires continued interaction with MHC molecules and cytokine support. (c) Upon antigen recognition in the lymph node, naive T cells are primed by dendritic cells. This process requires interaction between MHC and T cell receptor and coreceptor as well as between costimulatory molecules and cytokines provided by the dendritic cell. Both mouse and human dendritic cells are present and can in theory activate naive T cells, provided that costimulatory molecules and cytokines are sufficiently cross-reactive. (d ) Finally, cytotoxic T cells eliminate their target cells after recognition of MHC/peptide complexes through their T cell receptor. Two extremes of human T cell selection and function in HHLS mice that do not express human MHC on nonhematopoietic cells are depicted on the right and left side of the figure, where human T cells consistently interact with either mouse or human MHC. However, in the HHLS xenogeneic setting, some interaction with respective mouse or human MHC likely occurs at every step, leading to inefficient and possibly inappropriate T cell reactivity (symbolically depicted in the gray area in the middle).