Journal Article

Humanized mice for immune system investigation: progress, promise and challenges

Garcia-Martinez, J. Victor, Brehm, Michael A., Shultz, Leonard D., Greiner, Dale L.

2012

Overview

Key Points Severely immunodeficient mice engrafted with functional human cells and tissues, known as 'humanized' mice, facilitate progress in studies of human haematopoiesis, immunity, gene therapy, infectious diseases, cancer and regenerative medicine. Mice homozygous for the severe combined immunodeficiency ( scid ) gene mutation or for targeted mutations at the recombination-activating gene 1 ( Rag1 ) or Rag2 loci, that also have a targeted mutation at the interleukin-2 receptor γ-chain ( Il2rg ) locus, support high levels of engraftment and function of human haematopoietic stem cells (HSCs) and human immune systems. Advances in humanized mice over the past few years have included approaches to decrease host innate immune responses. In addition, humanized mouse models have benefited greatly from the identification of human species-specific molecules that are crucial for the engraftment and function of human haematopoietic and immune systems and the expression of these molecules in the immunodeficient recipient. The development of humanized mice with functional human immune systems (generated by the engraftment of human lymphoid tissues, HSCs or peripheral blood mononuclear cells) provides an opportunity to carry out translational research on human immunity and autoimmune diseases, and for the study of the biology of the human pathogens responsible for AIDS and several other human-specific infectious diseases. Humanized mice are being used as hosts for primary human tumours for studies of tumour growth and metastasis and for experimental cancer therapy. The phenotypical 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 are supported by studies in humanized mice remains promising. Additional genetic and technological modifications continue to accelerate progress towards the development of a robust functional human immune system in humanized mice. This article provides a comprehensive overview of the recent advances in the development and use of humanized mice. The authors consider the remaining challenges and the potential for new advances in our understanding of human immunology through the use of these mice. Significant advances in our understanding of the in vivo functions of human cells and tissues and the human immune system have resulted from the development of 'humanized' mouse strains that are based on severely immunodeficient mice with mutations in the interleukin-2 receptor common γ-chain locus. These mouse strains support the engraftment of a functional human immune system and permit detailed analyses of human immune biology, development and functions. In this Review, we discuss recent advances in the development and utilization of humanized mice, the lessons learnt, the remaining challenges and the promise of using humanized mice for the in vivo study of human immunology.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/1647/334/1874/345 / 631/250 / Animal models in research / Animals / Biomedical and Life Sciences / Biomedical research / Biomedicine / Cytokines / Disease Models, Animal / Genetically modified mice / Hematopoietic Stem Cell Transplantation / Humans / Immune system / Immune System - physiology / Immunodeficiency / Immunological research / Immunology / Innovations / Interleukin 2 / Interleukin Receptor Common gamma Subunit - genetics / Kinases / Lymphatic system / Medical research / Medicine, Experimental / Mice / Mice, SCID - genetics / Mice, SCID - immunology / Mice, Transgenic / Monkeys & apes / Mutation / Physiological aspects / review-article / Rodents / Rodents as laboratory animals