Review Article | Published:

Humanized mice in translational biomedical research

Nature Reviews Immunology volume 7, pages 118130 (2007) | Download Citation


The culmination of decades of research on humanized mice is leading to advances in our understanding of human haematopoiesis, innate and adaptive immunity, autoimmunity, infectious diseases, cancer biology and regenerative medicine. In this Review, we discuss the development of these new generations of humanized mice, how they will facilitate translational research in several biomedical disciplines and approaches to overcome the remaining limitations of these models.

Key points

  • There is a growing need for animal models to carry out in vivo studies of human biological systems without putting individuals at risk. Severely immunodeficient mice engrafted with human cells and tissues, known as 'humanized' mice, facilitate progress in studies of human haematopoiesis, immunity, gene therapy, infectious diseases, cancer and regenerative medicine.

  • Advances in the generation of humanized mice have depended on a systematic progression of genetic modifications in immunodeficient mouse hosts and on improvements in engraftment techniques.

  • Mice homozygous for the severe combined immunodeficiency (scid) gene mutation or for targeted mutations at the recombination-activating gene 1 (Rag1) or Rag2 loci, accompanied by a targeted mutation at the interleukin-2 receptor γ-chain (Il2rg) locus, support greatly increased engraftment and function of human haematopoietic stem cells (HSCs) and peripheral-blood mononuclear cells (PBMCs) compared with previous immunodeficient mouse models.

  • The development of immunodeficient mice that are humanized by engraftment of human lymphoid tissues, HSCs and PBMCs provides an opportunity to carry out translational research on human immunity and autoimmune diseases. These models are also being used to study the biology of human pathogens responsible for AIDS and several other infectious diseases.

  • Humanized mice are being increasingly used as hosts for human malignant cells in studies of carcinogenesis, tumour metastasis and cancer therapy. The phenotypic and functional characterization of human tumour stem cells is also being advanced through the study of humanized mice.

  • The potential for new advances in our understanding of human immunology and other areas of human biology that is supported by studies in humanized mice remains promising. Additional genetic and technological modifications will accelerate progress towards the development of a functional human immune system in mice.

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We thank E. Leiter, D. Serreze, M. Berry and A. Rossini for valuable discussions. We are supported by the β-Cell Biology Consortium and Autoimmunity Prevention Centers of the National Institutes of Health (NIH; USA), the Juvenile Diabetes Research Foundation (International), the American Diabetes Association, and the Diabetes Endocrinology Research Center, the National Cancer Institute Center, the National Institute of Allergy and Infectious Diseases and the National Heart, Lung and Blood Institute of the NIH. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

Author information


  1. The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA.

    • Leonard D. Shultz
  2. RIKEN, Research Center for Allergy and Immunology, Yokahama Institute, 1-7-22 Suehiro-cho, Tsurumi-Ku, Yokohama, Kanagawa, 230-0045, Japan.

    • Fumihiko Ishikawa
  3. University of Massachusetts Medical School, 373 Plantation Street, Biotech 2, Suite 218, Worcester, Massachusetts 01605, USA.

    • Dale L. Greiner


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Competing interests

Leonard D. Shultz and Dale L. Greiner are consultants for and receive financial support from Viacell, Inc. and Pfizer, Inc.

Corresponding author

Correspondence to Leonard D. Shultz.


Severe combined immunodeficiency

(scid). Mice homozygous for the scid mutation at the protein kinase, DNA activated, catalytic polypeptide (Prkdcscid) locus have a complete absence of mature T and B cells.


The spontaneous rearrangement of T- and B-cell receptors in scid mice, leading to the generation of mature T and B cells.

Recombination-activating gene 1 (Rag1) and Rag2

Two linked genes in which targeted mutations result in the complete inability to generate T and B cells expressing antigen-specific receptors.

Nude mice

Mice homozygous for a mutation in the forkhead box N1 (Foxn1) gene, which causes both hairlessness and impaired development of the thymus, resulting in an inability to generate mature T cells.

SCID-hu mice

Severe combined immunodeficiency (scid) mice engrafted with human fetal liver and thymus tissue under the renal capsule.

Hu-SRC-SCID mice

Severe combined immunodeficiency (scid) mice that have been sublethally irradiated and injected with human haematopoietic stem cells (HSCs). The HSCs are obtained from three main sources: bone marrow, umbilical cord blood or granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood, which contains large numbers of human HSCs.


An immune reactivity of cells or antibody from one animal directed against cells or tissues of a different species.

NOD/SCID-hu BLT mice

(BLT mice). Non-obese diabetic (NOD)-severe combined immunodeficiency (scid) mice engrafted with human fetal liver (L) and thymus (T) under the renal capsule. Three weeks later, mice are irradiated and then injected with a suspension of CD34+ cells from the same human fetal liver sample. The injected fetal liver cells seed to the mouse bone marrow (B).

Graves' disease

A type of autoimmune disease in which autoantibodies produced by the immune system overstimulate the thyroid gland, causing hyperthyroidism.


A term used for T-cell receptor (TCR)-transgenic mice generated by retrovirus-mediated transduction of haematopoietic stem cells (HSCs) with a vector carrying a TCR transgene. These transduced HSCs are then injected into conditioned mice to reconstitute the mice with T cells expressing the TCR transgene.


Refers to the ability of a non-stem cell to transform into a different type of cell lineage, or when an already partly differentiated stem cell creates cells of different lineages or cell types.


A tumour that derives from pluripotent germ cells, comprising disorganized tissues derived from all three embryonic germ layers (ectoderm, mesoderm and endoderm). It can arise spontaneously in the human gonads.

Myocardial infarction

An episode of acute cardiac ischaemia that leads to death of heart-muscle cells. It is usually caused by a thrombotic atherosclerotic plaque.

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