Humanized Mouse Models of Clinical Disease

Abstract

Immunodeficient mice engrafted with functional human cells and tissues, i.e., “humanized mice”, have become increasingly important as small pre-clinical animal models for the study of human diseases. Since the description of immunodeficient mice bearing mutations in the IL2 receptor common gamma chain (IL2rgnull) in the early 2000’s, investigators have been able to engraft murine recipients with human hematopoietic stem cells that develop into functional human immune systems. These mice can also be engrafted with human tissues such as islets, liver, skin, and most solid and hematologic cancers. Humanized mice are permitting significant progress in studies of human infectious disease, cancer, regenerative medicine, graft versus host disease, allergies, and immunity. Ultimately, use of humanized mice may lead to the implementation of truly “personalized” medicine in the clinic. This review discusses recent progress in the development and use of humanized mice, and highlights their utility for the study of human diseases.

Affinity of human IgG subclasses to mouse Fc gamma receptors

“…4 Many mouse disease models of different settings are available or can be developed. 5,6 Antibody therapies currently in development are usually based on humanized or human antibodies to reduce the possibility of immunogenicity, increase half-life and increase efficacy. 1 Cancer therapies often depend not only on the neutralizing capacity of the antibody's antigen binding fragments (Fabs) to eliminate pathogen or malignant cells, but also rely on interaction of the constant domain (Fragment crystallizable, Fc) with components of the immune system.…”

Mouse Models as Resources for Studying Infectious Diseases

“…57,58 Furthermore, differences between the mouse and human immune system may limit the utility of standard or modified mouse strains as models for studying host immune responses or disease pathogenesis. 59 To overcome these problems, the research community has used mice engrafted with human tissues to model human responses to infection. These human tissue xenografted mice take advantage of the fact that mice lacking a functional adaptive immune system (eg, SCID or RAG-1 knockout mice) are permissive for engraftment by human immune cells, while removal of other mouse genes, such as the common gamma chain of the interleukin-2 receptor, results in improved engraftment.…”

“…These models can be used to study multiple aspects of the host innate and adaptive immune response, and can also be engrafted with solid organ tissues from humans. 59,60 Furthermore, because immune cells and other tissues from the same individual can be used to generate cohorts of humanized mice, it is possible to test responses in sets of individuals carrying tissues from the same genetic background. 61 Although a detailed description of the different types of humanized mouse models, and the methods used in their development is beyond the scope of the present review, we refer the reader to several recent reviews that nicely summarize the current state of xenograft mouse development.…”

“…61 Although a detailed description of the different types of humanized mouse models, and the methods used in their development is beyond the scope of the present review, we refer the reader to several recent reviews that nicely summarize the current state of xenograft mouse development. 59,62 Mice with xenografted human immune systems have been used to study the pathogenesis of a wide range of infectious agents, including Plasmodium falciparum (malaria), Mycobacterium tuberculosis, dengue virus, and influenza virus. 59,61 These models have been particularly useful for studying HIV, including analysis of viral and host factors that promote viral replication, HIV interactions with the host immune response, and as platforms for testing therapeutic approaches for controlling or curing HIV infection.…”

“…59,62 Mice with xenografted human immune systems have been used to study the pathogenesis of a wide range of infectious agents, including Plasmodium falciparum (malaria), Mycobacterium tuberculosis, dengue virus, and influenza virus. 59,61 These models have been particularly useful for studying HIV, including analysis of viral and host factors that promote viral replication, HIV interactions with the host immune response, and as platforms for testing therapeutic approaches for controlling or curing HIV infection. 62 Although the majority of studies using xenografted mice have focused on human immune cells, these models can also be used to evaluate pathogen interactions with solid organs.…”