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

Abstract

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.

Figure 1. Approaches for engraftment of human immune systems in immunodeficient mice

Legend to Figure 1: a: To establish Hu-PBL-SCID mice, injection routes include IV, IP, and intrasplenic into adult recipients. To establish Hu-SRC-SCID mice, injection routes of HSC in adult recipients include IV and intrafemoral. b: Injection routes into newborn mice include facial vein, intracardiac, and intrahepatic. IP injection of HSC into newborn or adult recipients results in very low engraftment. To establish SCID-Hu mice, fetal liver and thymus fragments are implanted under the renal capsule into adult mice. To establish BLT mice, fetal liver and thymus fragments are implanted under the renal capsule into irradiated adult mice, and HSC derived from the same fetal liver are injected IV. HSC, haematopoietic stem cell; IP, intraperitoneal; IV, intravenous; PBL, peripheral blood lymphocytes.

Figure 2. Cytokines expressed transgenically in immunodeficient IL2rγ^null strains

Legend to Figure 2: Human cytokines that have been, or are currently under development, expressed transgenically in immunodeficient IL2rγ^null strains to enhance human hematopoietic cell engraftment and immune system development and function. SCF, stem cell factor, TPO, thrombopoietin, HSC, hematopoietic stem cell, GM-CSF, granulocyte macrophage colony stimulating factor, IL3, interleukin 3, EPO, erythropoietin, CSF-1, colony stimulating factor-1, BLyS/BAFF, B lymphocyte stimulator/B cell activating factor, IL7, interleukin 7, IL15, interleukin 15.