A “humanized” immune system rodent model is one in which human primary haematopoietic cells and tissues are implanted into an immunodeficient host that generate a functional human immune system.  The successful engraftment requires a fully immunodeficient host lacking B-cells, T-cells, and NK cells. Therefore, the preferred host models combine a nude/SCID (Rag2 KO) background with a mutation in the interleukin2 (IL2) receptor γchain locus (Il2rg KO).  There are several different technological approaches for the engraftment of a functional human immune system, which either include the engraftment of human peripheral blood lymphocytes (PBL) or haematopoietic stem cells (HSC)s or the implantation of fetal liver and thymus fragments are implanted under the renal capsule.

A humanized immune system provides an in-vivo model of human disease for tumor immunology, infectious disease, and autoimmunity, that promises to overcome the limitations of traditional animal models and boost the translation rate from target identification to the clinic. Studying cancer tumor progression and the development of mechanisms for evading and resisting the human immune response is enabled by having an in-vivo model of the human immune system and can paired with patient derived tumor xenografts (PDX). The humanized immune system, which is host for a variety of infectious diseases, provides a way to study diseases that are species specific or that don’t occur in animal models; for example,  HIV, S. enterica, Hepatitis  C,  and Ebola.  Additionally, these models have been known to show in some cases phenotypes of autoimmune diseases, but further development is needed.

Humanized rodent models allow for the study of immune responses to drug biologics, and cell and gene therapies, such as autologous induced pluripotent stem (iPS) cell therapies.  In one study, humanized rodents revealed differential immunogenicity and T-cell response to human iPS derived smooth muscle cells (SMCs) and retinal pigment epithelial (RPE) cell treatment (1). Humanized rodents can also be utilized to detect human T-cell depletion and cytokine release into the circulation, and therefore, provide a useful tool to aid in understanding and reducing the potential risks of cytokine release following biologic, cell and gene therapies.

To improve the humanization of the immune system, further genetic manipulation may be required.  For example, various human cytokines and growth factors enable the development of immune cells and expressing these improves the rate of engraftment and immune system development. There are currently a number of transgenic and knock-in mice that have been created and with increasing ease of gene editing, additional genetically modifications can be created in both mice and rats, for example, to address the lack of appropriate trafficking of human immune cells, or the rapid clearance of human red blood cells from circulation.

  1. Zhao et al (2015) Humanized Mice Reveal Differential Immunogenicity of Cells Derived from Autologous Induced Pluripotent Stem Cells. Cell Stem Cell.