The Utility of Super Immunodeficient Mice
Improvements in humanized mouse models for cancer are helping us more accurately recapitulate the in vivo function of human cells and tissues.
In recent years there has been a significant increase in the rate of discoveries in the immuno oncology field, which in turn has led to US Food and Drug Administrationapproval of several checkpoint inhibitors. There are now over 800 active clinical trials in the US alone for immunomodulating combination therapies.
As successes mount in cancer immunotherapy, there is an ever growing need for well-characterized preclinical models with functional immune systems. (Check out this upcoming webinar on continuous improvements in humanized mouse models.)
One approach is to use models of syngeneic tumors in immunocompetent mice as human surrogates to evaluate the efficacy of immune-targeting agents against the murine immunological target. This is a reasonable approach with immunotherapeutic agents designed to affect the murine immune system. But it does not allow for evaluation of human specific therapeutics and points to an unmet need for preclinical oncology models that include at least elements of the human immune system.
Historically, immunodeficient mice have been used to grow human tumor xenografts. This has allowed for evaluation of therapies designed specifically for human tumor targets. Currently the need in preclinical models for immuno-oncology requires the incorporation of the human immune system in mouse oncology models. This will allow for evaluation of therapies targeting the inhibition or activation of human immune cell biology. The now conventional nude mouse has been shown to be an inadequate host of human immune cell populations and this has led to the use of super-immunodeficient mouse strains for successful engraftment of human immune cell populations leading to what are frequently referred to as humanized mice
Humanized mice as pre-clinical models for the in vivo study of human immune cells and tissues have been under development for over 30 years. A challenge in this effort is the appearance of graft versus host disease (GvHD) upon engraftment of human immune cell populations. The appearance of GvH disease negatively impacts the durability and utility of these mice.
But an important technological advancement in the design of humanized mice occurred in the early 2000s when investigators created immunodeficient NOD-scid IL2rg-/- mice (NOD scid gamma mice) that harbored targeted mutations in the IL-2 receptor common gamma chain (Il2rg) gene. The NOD scid gamma mouse is deficient in T, B and functional Natural Killer (NK) cells of the human immune system.
The use of NOD scid gamma mice deficient in T, B and NK cells for the first time permitted the generation of the humanized mouse with proliferating human T cells in a reasonably durable model. There are still limitations in these mice for mimicking the human immune system, but this certainly represents a step forward.
There are two main approaches to humanizing mice via engraftment of functional human immune cells. The first one is engraftment of human peripheral blood mononuclear cells (PBMC) which predominately engrafts mature human CD3 T cells and is useful for the study of mature T cell function. This model allows for a short (several weeks) window for studying cancer models and then progresses to a lethal xenogeneic graft-vs-host disease (xeno-GvHD) endpoint. The onset of xeno-GvHD correlates directly with level of human cell engraftment.
A second humanizing protocol involves engraftment of hematopoietic stem cells. It is highly dependent on the age of the recipient at the time of engraftment and results in the engraftment of T and B cells and a humanized mouse with considerably longer durability than a PBMC engrafted host.
Both models lack NK and MDSC immune populations so the current humanized mouse models do not represent platforms with fully functional human immune systems. Charles River along with other companies understands the importance of developing new animal models for immunooncology and have been working on bringing these new strains and models to the scientific community.
These mice are now being used as in vivo models for the study of human hematopoiesis, immunity, regeneration, stem cell function, cancer, and human-specific infectious agents without putting patients at risk. Additional modifications of these model systems including further genetic manipulation of the murine host continue to improve the ability of humanized mice to more accurately recapitulate the in vivo function of human cells and tissues.