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

The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA.
Nature Reviews Immunology (Impact Factor: 34.99). 10/2012; 12(11):786-98. DOI: 10.1038/nri3311
Source: PubMed


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.

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    • "While these models represent a major advance, they do not fully recapitulate the genetic diversity of the human Fc-receptor system and rely on triggering effector functions through mouse immune cells. As an alternative to transgenic mice, humanized mouse models, in which the human immune system is grafted onto immunodeficient mouse backgrounds, such as NOD/SCID/gc or Rag2/gc knockout mice, have been developed and represent valuable in vivo model systems to study the interaction of human pathogens with the human immune system (Bournazos et al., 2014; Halper-Stromberg et al., 2014; Horwitz et al., 2013; Shultz et al., 2012). With respect to studying human (auto)antibody activity in humanized mice, however, the presence of mouse activating Fcg receptors, which can interact with different human IgG subclasses , represents a major caveat (Lux and Nimmerjahn, 2013; Lux et al., 2014). "
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    ABSTRACT: Immunoglobulin G (IgG) antibodies are major drivers of autoimmune pathology, but they are also used in the form of intravenous IgG (IVIg) therapy to suppress autoantibody activity. To identify the pathways underlying human autoantibody and IVIg activity, we established a humanized mouse model of an autoantibody-dependent autoimmune disease responding to treatment with IVIg preparations. We show that the human IgG subclass strongly impacts autoantibody activity and that the Fc-receptor genotype of the human donor immune system further modulates autoantibody activity. Human mononuclear phagocytes were responsible for autoantibody activity, and IVIg therapy was able to suppress disease pathology in an Fc-fragment-dependent manner. While highly sialylated IgG glycovariants were essential for IVIg activity, it was independent of the Fc-receptor genotype and did not result in a general block of activating or the neonatal Fc-receptor. These findings may help in the development of strategies to block autoantibody and enhance therapeutic IVIg activity in humans.
    Cell Reports 10/2015; 13(3). DOI:10.1016/j.celrep.2015.09.013 · 8.36 Impact Factor
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    • "Mouse models humanized for components of the immune system (HIS) are based on the xenotransplantation of tissues supporting longterm production of human hematopoietic cells into permissive, immuno-deficient animals. Strategies to generate HIS mice have been largely optimized over the past three decades (Shultz et al. 2012). Despite residual limitations, HIS mice are seen as attractive platforms to perform prospective in vivo analysis of human leucocyte ontogeny, function and reactivity in preclinical settings. "

    Transgenic Research 09/2015; DOI:10.1007/s11248-015-9904-6 · 2.32 Impact Factor
    • "Immunodeficient mice that have been engrafted with human primary hematopoietic cells and tissues generating a functional human immune system in these mice are well-established examples of humanized mice. These models have been successfully used to investigate infectious diseases, autoimmune disorders, and tumors (Shultz et al., 2012). "
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    ABSTRACT: Many well-defined animal models for human disease are employed in modern preclinical and pathophysiology-driven research. However, the scientific community across all fields of modern biomedicine has become aware of weaknesses in current preclinical animal modeling. Here, we have outlined several strategies that have already been set into action to overcome the translational gap that is common to all current preclinical modeling of human disease.
    Principles of Translational Science in Medicine - From Bench to Bedside, 2nd Ed. edited by Martin Wehling, 04/2015: chapter Animal Models: Value and Translational Potency: pages 83 - 90; Academic Press., ISBN: 978-0-12-800721-1
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