Article

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

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.

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    • "This is particularly true for mechanisms of central B cell tolerance. Immunodeficient mice transplanted with human hematopoietic stem cells (HSCs) provide a tool to study the human immune system in greater depth (Manz and Di Santo, 2009; Ito et al., 2012; Shultz et al., 2012). By using immunodeficient mice of the BALB/c-Rag2 null IL2Rγ null strain (BRG or BAL- B/c-DKO), we have previously established a robust humanized mouse (hu-mouse) model for the analysis of human B cells and their development (Lang et al., 2011, 2013). "
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    ABSTRACT: The mechanisms by which B cells undergo tolerance, such as receptor editing, clonal deletion, and anergy, have been established in mice. However, corroborating these mechanisms in humans remains challenging. To study how autoreactive human B cells undergo tolerance, we developed a novel humanized mouse model. Mice expressing an anti-human Igκ membrane protein to serve as a ubiquitous neo self-antigen (Ag) were transplanted with a human immune system. By following the fate of self-reactive human κ(+) B cells relative to nonautoreactive λ(+) cells, we show that tolerance of human B cells occurs at the first site of self-Ag encounter, the bone marrow, via a combination of receptor editing and clonal deletion. Moreover, the amount of available self-Ag and the genetics of the cord blood donor dictate the levels of central tolerance and autoreactive B cells in the periphery. Thus, this model can be useful for studying specific mechanisms of human B cell tolerance and to reveal differences in the extent of this process among human populations.
    No preview · Article · Dec 2015 · Journal of Experimental Medicine
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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.
    Full-text · Article · Oct 2015 · Cell Reports
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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. "

    Full-text · Article · Sep 2015 · Transgenic Research
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