Use of Humanized Mice to Study the Pathogenesis of Autoimmune and Inflammatory Diseases

Abstract

Animal models of disease have been used extensively by the research community for the past several decades to better understand the pathogenesis of different diseases as well as assess the efficacy and toxicity of different therapeutic agents. Retrospective analyses of numerous preclinical intervention studies using mouse models of acute and chronic inflammatory diseases reveal a generalized failure to translate promising interventions or therapeutics into clinically-effective treatments in patients. Although several possible reasons have been suggested to account for this generalized failure to translate therapeutic efficacy from the laboratory bench to the patient’s bedside, it is becoming increasingly apparent that the mouse immune system may not adequately recapitulate the immuno-pathological mechanisms observed in human diseases. Indeed, it is well-known that >80 major differences exist between mouse and human immunology; all of which contribute to significant differences in immune system development, activation and responses to challenges in innate and adaptive immunity. This inconvenient reality has prompted investigators to attempt to humanize the mouse immune system in order to address important, human-specific questions that are impossible to study in patients. The successful long-term engraftment of human hemato-lymphoid cells in mice would provide investigators with a relatively inexpensive, small animal model to study clinically-relevant mechanisms as well as facilitate the evaluation of human-specific therapies in vivo. The discovery that targeted mutation of the IL-2 receptor common gamma chain in lymphopenic mice allows for the long-term engraftment of functional human immune cells has advanced greatly our ability to humanize the mouse immune system. The objective of this review is to present a brief overview of the recent advances that have been made in the development and use of humanized mice with special emphasis on autoimmune and chronic inflammatory diseases. In addition, we discuss current challenges and possible solutions for utilizing these unique mouse models to define the human-specific immuno-pathological mechanisms responsible for the induction and perpetuation of chronic gut inflammation.

Humanized Mice as Unique Tools for Human-Specific Studies

“…These inventions cascaded into a series of immunodeficient mice and their variants (BRG, NOG, NRG) (Ali et al 2012; Grover et al 2017; Ishikawa et al 2005; Katano et al 2014; Koboziev et al 2015; Shultz et al 2005) being innovated which enabled in-depth analysis in research areas, such as human hematopoiesis (Rongvaux et al 2011; Yong et al 2016), innate and adaptive immunity (Brehm et al 2010; Pearson et al 2008), autoimmunity (Gunawan et al 2017; Viehmann Milam et al 2014), infectious disease (Keng et al 2015; Lüdtke et al 2015; Wege et al 2012), cancer biology (Chang et al 2015; Her et al 2017; Morton et al 2016), and GvHD (King et al 2008; Kirkiles-Smith et al 2009; Zhao et al 2015), in-turn, facilitating the development of therapeutic agents and novel vaccines. An overview of genotypic and physiological characteristics of each model is outlined in Tables 1 and 2.…”

A humanized mouse model to study mast cells mediated cutaneous adverse drug reactions

“…Human MC producing humice that have so far been described are based on a NOD‐scid IL2rg null SCF/GM‐CSF/IL‐3 (NSG‐SGM3) strain of mice engrafted with human umbilical cord blood or thymus, liver, and hematopoietic stem cells and which constitutively express GM‐CSF and IL‐3 have been reported . However, long‐term exposure and constitutive expression of human cytokines in humice can be challenging as non‐physiological effects are sometimes observed, including deleterious effects on the human stem cell compartments, and progressive anaemia and polarization of the immune system . Therefore, in our model, we performed a hydrodynamic gene delivery of human cytokines into humice, and found that we could markedly enhance the reconstitution and function of human immune cells subsets, without any undesirable side effects .…”

Humanized mice: A brief overview on their diverse applications in biomedical research

“…The development of peripheral lymph nodes and gut-associated lymphoid tissue (GALT) in the present humanized immune system mice is imperfect with defective formation of important substructures such as the germinal center. Efforts to address these problems are being made to reproduce the structure and function of human immune system more faithfully (reviewed in [Koboziev et al, 2015;Theocharides, Rongvaux, Fritsch, Flavell, & Manz, 2016]).…”