Humanization of Immunodeficient Animals for the Modeling of Transplantation, Graft Versus Host Disease, and Regenerative Medicine

Abstract

The humanization of animals is a powerful tool for the exploration of human disease pathogenesis in biomedical research, as well as for the development of therapeutic interventions with enhanced translational potential. Humanized models enable us to overcome biologic differences that exist between humans and other species, while giving us a platform to study human processes in vivo. To become humanized, an immune-deficient recipient is engrafted with cells, tissues, or organoids. The mouse is the most well studied of these hosts, with a variety of immunodeficient strains available for various specific uses. More recently, efforts have turned to the humanization of other animal species such as the rat, which offers some technical and immunologic advantages over mice. These advances, together with ongoing developments in the incorporation of human transgenes and additional mutations in humanized mouse models, have expanded our opportunities to replicate aspects of human allotransplantation and to assist in the development of immunotherapies. In this review, the immune and tissue humanization of various species is presented with an emphasis on their potential for use as models for allotransplantation, graft versus host disease, and regenerative medicine.

Super-Treg: Toward a New Era of Adoptive Treg Therapy Enabled by Genetic Modifications

“…Immune humanized immunodeficient animal models will continue to be useful to address many questions in preclinical studies ( 211 ). Moreover, human and/or patient organoids, may gain more importance and are promising candidates for examining Treg function in disease models ( 212 ).…”

Advances in Genome Editing and Application to the Generation of Genetically Modified Rat Models

“…Transgenic rats for human SIRPa to inhibit phagocytosis in human cells have been described in recent years (Goto et al, 2016;Jung et al, 2016;Ménoret et al, 2020). These rats have been used in humanization of their immune system and/or other tissues in transplantation and regenerative medicine settings (for a review, see Adigbli et al, 2020) and in cancer research (He et al, 2019). In these models as in others, the larger size of the rat allows to do analysis of human cells of the blood more frequently than in mice.…”

Development of LT-HSC-Reconstituted Non-Irradiated NBSGW Mice for the Study of Human Hematopoiesis In Vivo

“…The model is technically easy to use and achieves robust multilineage reconstitution of lymphoid and myeloid human cells which persist long-term. For decades, achieving this has challenged several of the available HIS mouse models, which are unable to support both engraftment of all lymphocytes and myeloid cells and maturation and survival into the long-term ( 22 ). Human thymocytes develop in a humanized thymic microenvironment and both naïve and memory CD4 + and CD8 + T cells repopulate in the periphery.…”