Humanized Chimeric Rodent Models

Current pre-clinical animal models have been- useful to study the many aspects of mammalian biological systems, however translating discoveries in rodents into clinical applications often falls short due to species related differences in biology, drug ADME (absorption, distribution, metabolism, and excretion), and toxicity, leading to the failure of drug candidates.  In order to overcome these limitations “humanized” rodent models haven been developed and they are becoming a crucial tool for researchers, toxicologists, and pharmacologists which provides confidence in their ADME-Tox findings, drug safety assessments and may prevent drug failures.

There are two approaches for creating humanized models; tissue or cellular humanization and genetic humanization. Tissue or cellular humanization involves replacing cells or entire organs with human cells in order to develop a functioning human liver or immune system within the model organism. Genetic humanization uses genetic modification to replace a particular endogenous gene or genes, such as the Cyp2d, which are is involved in drug metabolism, with their human orthologs.

STUDIES AND APPLICATIONS

  1. Humanized mice for immune system investigation: progress, promise and challenges
    Abstract: Significant advances in our understanding of the in vivo functions of human cells and tissues and the human immune system have resulted from the development of ‘humanized’ mouse strains that are based on severely immunodeficient mice with mutations in the interleukin-2 receptor common γ-chain locus. These mouse strains support the engraftment of a functional human immune system and permit detailed analyses of human immune biology, development and functions. In this Review, recent advances in the development and utilization of humanized mice, the lessons learnt, the remaining challenges and the promise of using humanized mice for the in vivo study of human immunology are discussed.
    Shultz, et al. Nature Reviews Immunology. 2012 November. 12(11), 786–798.
  2. Immunodeficient mouse model for human hematopoietic stem cell engraftment and immune system development.
    Summary: Immunodeficient mice engrafted with human immune systems provide an exciting model to study human immunobiology in an in vivo setting without placing patients at risk. The essential parameter for creation of these “humanized models” is engraftment of human hematopoietic stem cells (HSC) that will allow optimal development of human immune systems.  This paper describes a protocol for the co-implantation of human HSC with autologous fetal liver and thymic tissues into immunodeficient mice to create a humanized model with optimal human T cell development. This model, often referred to as the Thy/Liv or BLT (bone marrow, liver, thymus) mouse, develops a functional human immune system, including HLA-restricted human T cells, B cells and innate immune cells.
    Aryee, et al. Methods in Molecular Biology. 2015 June. 1185, 267–278.
  3. Humanized Mice Reveal Differential Immunogenicity of Cells Derived from Autologous Induced Pluripotent Stem Cells
    Summary: Induced pluripotent stem cells (iPSCs) could become a renewable source of autologous cells for transplantation into human patients. While it has been assumed that the immune rejection problem challenging hESCs could be mitigated by the development of patient-specific hiPSCs without the concern of immune rejection, recent studies have shown that certain cell types derived from mouse iPSCs such as cardiomyocytes are immunogenic in syngeneic recipients. Therefore, as an integral part of the effort to develop hiPSCs into human cell therapy, it is important to evaluate the immunogenicity of hiPSC-derived cells in the context of an autologous human immune system. To address this bottleneck, we established humanized mouse models that are efficiently reconstituted with both T and B cells as well as macrophages and dendritic cells required for antigen presentation. Differential immunogenicity and T-cell response to human iPS derived smooth muscle cells (SMCs) and retinal pigment epithelial (RPE) cell treatment where shown. Humanized mice can mount vigorous immune rejection of allogeneic cells derived from hESCs. Therefore, the humanized mice provide a unique opportunity to examine the immunogenicity of autologous cells derived from hiPSCs.
    Zhao, et al. Cell Stem Cell. 2015 September.  17;3 (353–359).