Humanized mice: Current states and perspectives

doi:10.1016/j.imlet.2012.03.009

Immunology Letters

Volume 146, Issues 1–2, 30 August 2012, Pages 1-7

https://doi.org/10.1016/j.imlet.2012.03.009 Get rights and content

Abstract

The development of chimeric mice bearing the components of a human immune system to serve as animal models for “human” diseases has been the goal of many years of research. In this review we will discuss the latest advances in this field, their remaining shortcomings and challenges to the generation of new models of mouse/human chimeras.

Highlights

► We describe the newest versions of humanized mice bearing a human immune system. ► We describe the limitations of these models, especially lymphocyte functions. ► We describe the current approaches to overcome these limitations. ► We focus on two approaches: HLA and human Sirpa expression by murine hosts.

Introduction

For over 20 years, we have endeavored to establish chimeric mice that express the components of a human immune system to serve as animal models for “human” diseases, including HIV and EBV, and for designing vaccines. Original strategies for creating murine hosts that bear human immune cells involved the adoptive transfer of mature human immune cells into severe combined immunodeficient (SCID) recipients; these are referred to as hu-PBL models [1]. Another approach involved the reconstitution of a human immune system in SCID mice through engraftment of human hematopoietic precursor cells; these are referred to as hu-HSC models [2]. However, those models were limited; the hu-PBL was associated with the graft-versus-host reaction [3] and the hu-HSC exhibited poor peripheral T cell reconstitution [4]. These approaches were greatly improved with the creation of new types of immunocompromised mice. Improved mouse strains had deficiencies in T and B cells, like mice deficient in recombination activating gene (RAG^−/−) or SCID mice, but they were also deficient in natural killer (NK) cells due to a deficiency for the common γ chain (γc) of the IL-2 receptor shared by receptors for IL-4, -7, -9, -15, and -21 (reviewed in [5]). These new γc^−/− hosts either RAG^−/− or SCID were created in various host genetic backgrounds, including non-obese diabetic (NOD) or BALB/c. To establish chimeric mice, they have been reconstituted with different sources of human cells (peripheral blood, cord blood, fetal liver, or bone marrow), injected through different routes (intravenously or intrahepatically), tested in adults or newborns, that were subjected to different myelo-ablative regimens (irradiation or busulfan). Finally, two main types of hu-HSC chimeras were obtained: the “Human Immune system” (HIS) model and the “Bone Marrow/Liver/Thymus” (BLT) model. HIS models consist of human hematopoietic progenitors engrafted into murine hosts, including NOD/SCID/γc^−/− (NSG) [6], [7], [8], NOD/RAG^−/−/γc^−/− (NRG) [9] or RAG^−/− γc^−/− BALB/c (RG) [10]. The BLT models consist of a triple xenograft of thymus, liver, and hematopoietic progenitors; all the engrafted cells are collected from the bone marrow or liver from a single human fetus [11]. This review will focus on the latest data from the HIS models, and we will discuss the opportunities provided by new strategies for improving these chimeras.

Section snippets

The immune reconstitution of alympoid mice

The first results obtained from the reconstitution of NSG, NRG, or RG with human CD34⁺ hematopoietic progenitors represented a considerable improvement over reconstitutions in γc^+/+ mice [12]. The new chimeras possessed human T cells, B cells, NK cells, macrophages, and dendritic cells (DCs). Furthermore, the use of neonate recipients and human hematopoietic progenitors derived from fetal liver or cord blood appeared to offer superior human immune reconstitution compared to engraftment of adult

Optimization of SIRPα–CD47 interactions in HIS mice

The empirical observation that immune reconstitution with human HSCs was superior in NOD compared to other mouse strains [74], [75] was initially attributed to an alternate innate immunity in these host mice [76]. Genomic studies showed that this permissive phenotype of NOD mice was localized to the Idd13 locus, which encodes part of the Sirpα gene. SIRPα is an immunoglobulin ‘superfamily’ transmembrane protein with an intracellular immunoreceptor tyrosine-based inhibition motif (ITIM domain),

HLA expression in HIS mice

Another crucial aspect of HIS mice is the lack of HLA-restriction of human T cells. This impacts T cell numbers and T and B cell functions (see above). Indeed, though not proven formally, it is likely that thymus positive selection of human thymocytes is mediated by murine MHC-p/human TCR signaling that results from murine TEC/human thymocyte interactions. This results in H-2-restricted, instead of HLA-restricted, human T cells. Accordingly, a recent study showed that reconstitution of RG IAβ^−/−

Conclusions

Although engraftment of immunodeficient γc^−/− mice with human HSC leads to the presence of both myeloid and lymphoid lineages, many caveats remain in the original models. For example, the human reconstitution fails to be maintained over the long-term, myeloid development is poor, and T, B, and NK cell reconstitutions are quantitatively and qualitatively weak. However, many improvements have been reported; for example, the expression of human growth factors has improved human cell production and

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ReviewHumanized mice: Current states and perspectives

Abstract

Highlights

Introduction

Section snippets

The immune reconstitution of alympoid mice

Optimization of SIRPα–CD47 interactions in HIS mice

HLA expression in HIS mice

Conclusions

Adv Immunol

Curr Opin Immunol

Blood

Blood

Blood

Blood

Hum Immunol

Blood

Blood

Blood

Blood

Blood

Immunobiology

Exp Hematol

Semin Immunol

Blood

Clin Immunol

Immunol Today

Virology

Blood

Immunol Lett

Trends Immunol

Exp Hematol

Curr Opin Immunol

Human T cells in the SCID-hu mouse are phenotypically normal and functionally competent

J Immunol

Humanized mice: are we there yet

J Exp Med

Handgretinger R. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2Rγnull mice engrafted with mobilized human hemopoietic stem cells

J Immunol

Development of a human adaptive immune system in cord blood cell-transplanted mice

Science

Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1

Nat Med

Renaissance for mouse models of human hematopoiesis and immunobiology

Nat Immunol

Parameters for establishing humanized mouse models to study human immunity: analysis of human hematopoietic stem cell engraftment in three immunodeficient strains of mice bearing the IL2Rγnull mutation

Clin Immunol

Long-term human CD34+ stem cell-engrafted nonobese diabetic/SCID/IL2Rγnull mice show impaired CD8+ T cell maintenance and a functional arrest of immature NK cells

J Immunol

Human thrombopoietin knockin mice efficiently support human hematopoiesis in vivo

Proc Natl Acad Sci USA

Differential secondary reconstitution of in vivo-selected human SCID-repopulating cells in NOD/SCID versus NOD/SCID/γ chainnull mice

Bone Marrow Res

Functional human T lymphocyte development from cord blood CD34+ cells in nonobese diabetic/Shi-scid, IL-2 receptor γ null mice

J Immunol

Humanized mice in translational biomedical research

Nat Rev

The analysis of the functions of human B and T cells in humanized NOD/shi-scid/γcnull (NOG) mice (hu-HSC NOG mice)

Int Immunol

Expression of human cytokines dramatically improves reconstitution of specific human-blood lineage cells in humanized mice

Proc Natl Acad Sci USA

Human IL-3/GM-CSF knock-in mice support human alveolar macrophage development and human immune responses in the lung

Proc Natl Acad Sci USA

IL-15 transpresentation promotes both human T-cell reconstitution and T-cell-dependent antibody responses in vivo

Proc Natl Acad Sci USA

Development of functional human NK cells in an immunodeficient mouse model with the ability to provide protection against tumor challenge

PLoS ONE

Human immune system mice: current potential and limitations for translational research on human antibody responses

Immunol Res

Disseminated and sustained HIV infection in CD34+ cord blood cell-transplanted Rag2−/−γc−/− mice

Proc Natl Acad Sci USA

Review
Humanized mice: Current states and perspectives

Handgretinger R. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2Rγ^null mice engrafted with mobilized human hemopoietic stem cells

Parameters for establishing humanized mouse models to study human immunity: analysis of human hematopoietic stem cell engraftment in three immunodeficient strains of mice bearing the IL2Rγ^null mutation

Long-term human CD34⁺ stem cell-engrafted nonobese diabetic/SCID/IL2Rγ^null mice show impaired CD8⁺ T cell maintenance and a functional arrest of immature NK cells

Differential secondary reconstitution of in vivo-selected human SCID-repopulating cells in NOD/SCID versus NOD/SCID/γ chain^null mice

Functional human T lymphocyte development from cord blood CD34⁺ cells in nonobese diabetic/Shi-scid, IL-2 receptor γ null mice

The analysis of the functions of human B and T cells in humanized NOD/shi-scid/γc^null (NOG) mice (hu-HSC NOG mice)

Disseminated and sustained HIV infection in CD34⁺ cord blood cell-transplanted Rag2^−/−γc^−/− mice