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.

Immunodeficient mice engrafted with human peripheral blood mononuclear cells (PBMCs) support preclinical studies of human pathogens, allograft rejection, and human T‐cell function. However, a major limitation of PBMC engraftment is development of acute xenogeneic graft‐versus‐host disease (GVHD) due to human T‐cell recognition of murine major histocompatibility complex (MHC). To address this, we created 2 NOD‐scid IL‐2 receptor subunit γ (IL2rg)null (NSG) strains that lack murine MHC class I and II [NSG–β‐2‐microglobulin (B2M)null (IA IE)null and NSG‐(Kb Db)null (IAnull)]. We observed rapid human IgG clearance in NSG‐B2Mnull (IA IE)null mice whereas clearance in NSG‐(Kb Db)null (IAnull) mice and NSG mice was comparable. Injection of human PBMCs into both strains enabled long‐term engraftment of human CD4+ and CD8+ T cells without acute GVHD. Engrafted human T‐cell function was documented by rejection of human islet allografts. Administration of human IL‐2 to NSG‐(Kb Db)null (IAnull) mice via adeno‐associated virus vector increased human CD45+ cell engraftment, including an increase in human regulatory T cells. However, high IL‐2 levels also induced the development of GVHD. These data document that NSG mice deficient in murine MHC support studies of human immunity in the absence of acute GVHD and enable evaluation of human antibody therapeutics targeting human T cells.—Brehm, M. A., Kenney, L. L., Wiles, M. V., Low, B. E., Tisch, R. M., Burzenski, L., Mueller, C., Greiner, D. L., Shultz, L. D. Lack of acute xenogeneic graft‐versus‐host disease, but retention of T‐cell function following engraftment of human peripheral blood mononuclear cells in NSG mice deficient in MHC class I and II expression. FASEB J. 33, 3137–3151 (2019). http://www.fasebj.org

The balance between protective immunity and immunopathology often determines the fate of the virus-infected host. How rapidly virus is cleared is a function of initial viral load, viral replication rate, and efficiency of the immune response. Here, we demonstrate, with three different inocula of lymphocytic choriomeningitis virus (LCMV), how the race between virus replication and T cell responses can result in different disease outcomes. A low dose of LCMV generated efficient CD8 T effector cells, which cleared the virus with minimal lung and liver pathology. A high dose of LCMV resulted in clonal exhaustion of T cell responses, viral persistence, and little immunopathology. An intermediate dose only partially exhausted the T cell responses and resulted in significant mortality, and the surviving mice developed viral persistence and massive immunopathology, including necrosis of the lungs and liver. This suggests that for non-cytopathic viruses like LCMV, hepatitis C virus, and hepatitis B virus, clonal exhaustion may be a protective mechanism preventing severe immunopathology and death.

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.

Background Mast cells are a critical component of allergic responses in humans, and animal models that allow the in vivo investigation of their contribution to allergy and evaluation of new human-specific therapeutics are urgently needed. Objective We have developed a new humanized mouse model that supports human mast cell engraftment and human IgE-dependent allergic responses. Methods This model is based on the NOD-scid IL2rgnull SCF/GM-CSF/IL3 (NSG-SGM3) strain of mice engrafted with human thymus, liver and hematopoietic stem cells (termed BLT). Results Large numbers of human mast cells develop in NSG-SGM3 BLT mice and populate the immune system, peritoneal cavity, and peripheral tissues. The human mast cells in NSG-SGM3 BLT mice are phenotypically similar to primary human mast cells and express CD117, tryptase, and FcεRI. These mast cells undergo degranulation in an IgE-dependent and independent manner, and can be readily cultured in vitro for additional studies. Intradermal priming of engrafted NSG-SGM3 mice with a chimeric IgE containing human constant regions resulted in development of a robust passive cutaneous anaphylaxis (PCA) response. Moreover, we describe the first report of a human mast cell antigen-dependent passive systemic anaphylaxis (PSA) response in primed mice. Conclusions NSG-SGM3 BLT mice provide a readily available source of human mast cells for investigation of mast cell biology and a pre-clinical model of PCA and PSA that can be used to investigate the pathogenesis of human allergic responses and to test new therapeutics prior to their advancement to the clinic.