Humanized Mouse Models for Transplant Immunology

Abstract

Our understanding of the molecular pathways that control immune responses, particularly immunomodulatory molecules that control the extent and duration of an immune response, have led to new approaches in the field of transplantation immunology to induce allograft survival. These molecular pathways are being defined precisely in murine models and translated into clinical practice; however, many of the newly available drugs are human‐specific reagents. Furthermore, many species‐specific differences exist between mouse and human immune systems. Recent advances in the development of humanized mice, namely, immunodeficient mice engrafted with functional human immune systems, have led to the availability of a small animal model for the study of human immune responses. Humanized mice represent an important preclinical model system for evaluation of new drugs and identification of the mechanisms underlying human allograft rejection without putting patients at risk. This review highlights recent advances in the development of humanized mice and their use as preclinical models for the study of human allograft responses.

Humanized Mouse Models of Clinical Disease

“…Allograft rejection in humanized mice has been extensively studied for over two decades [for reviews, see (122–124)]. Historically the majority of studies were done in the Hu-PBL-SCID model but limited engraftment of human cell subsets other than CD3+ T cells can hinder rejection and results in variability between studies (122, 123).…”

“…Historically the majority of studies were done in the Hu-PBL-SCID model but limited engraftment of human cell subsets other than CD3+ T cells can hinder rejection and results in variability between studies (122, 123). However, immunodeficient mice transplanted with human skin were used to investigate therapeutic drugs such as cyclosporine and rapamycin to begin to identify the role that IFNγ-producing T cells have in graft survival as well as the mechanisms by which Tregs modulate the human T cell allograft response (122–124). …”

“…Humanized mouse models allow for the study of the cellular mechanisms of rejection of human islets by allogeneic immune responses and provide a preclinical environment to test new therapeutics (122–124). Interestingly, HSC-engrafted NSG and BRG animals have shown contrasting rejection of allogeneic human islet grafts, documenting the importance of which model system is used for experimentation.…”

“…Arterial transplantation followed by allogeneic PBMC injection leads to human cell infiltration and morphological changes within the graft associated with rejection [reviewed in (124)]. Similar to skin and islet allografts the rejection is associated with IFNγ production by allospecific T cells, which mediates neointima, or scarring within the blood vessels of the graft.…”

“…For example, blockade of either IL-6 or IL-1 signaling reduced graft injury. Tregs have also been found to block arterial graft rejection and prevent the development of arteriosclerosis in BRG mice transplanted with human aortic grafts and injected with PBMC (124). …”