Potential Applications and Perspectives of Humanized Mouse Models

As medical and pharmacological technology advances, new and complex modalities of disease treatment that are more personalized and targeted are being developed. Often these modalities must be validated in the presence of critical components of the human biological system. Given the incongruencies between murine and human biology, as well as the human-tropism of certain drugs and pathogens, the selection of animal models that accurately recapitulate the intricacies of the human biological system becomes more salient for disease modeling and preclinical testing. Immunodeficient mice engrafted with functional human tissues (so-called humanized mice), which allow for the study of physiologically relevant disease mechanisms, have thus become an integral aspect of biomedical research. This review discusses the recent advancements and applications of humanized mouse models on human immune system and liver humanization in modeling human diseases, as well as how they can facilitate translational medicine. Expected final online publication date for the Annual Review of Animal Biosciences, Volume 10 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Therapeutic Efficacy of Human Embryonic Stem Cell–Derived Endothelial Cells in Humanized Mouse Models Harboring a Human Immune System

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.113.302462 ◽

2013 ◽

Vol 33 (12) ◽

pp. 2839-2849 ◽

Cited By ~ 9

Author(s):

Heung-Mo Yang ◽

Sung-Hwan Moon ◽

Young-Sil Choi ◽

Soon-Jung Park ◽

Yong-Soo Lee ◽

...

Keyword(s):

Endothelial Cells ◽

Stem Cell ◽

Immune System ◽

Mouse Models ◽

Human Embryonic Stem Cell ◽

Embryonic Stem ◽

Human Immune System ◽

Humanized Mouse ◽

Human Immune ◽

Humanized Mouse Models

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Recent Updates on Mouse Models for Human Immunodeficiency, Influenza, and Dengue Viral Infections

Viruses ◽

10.3390/v11030252 ◽

2019 ◽

Vol 11 (3) ◽

pp. 252 ◽

Cited By ~ 7

Author(s):

Vinodhini Krishnakumar ◽

Siva Durairajan ◽

Kalichamy Alagarasu ◽

Min Li ◽

Aditya Dash

Keyword(s):

Mouse Models ◽

Viral Infections ◽

Antiviral Agents ◽

Immunological Response ◽

Innate Immune ◽

Humanized Mouse ◽

Species Barrier ◽

Knock Out ◽

Immunodeficient Mice ◽

Humanized Mouse Models

Well-developed mouse models are important for understanding the pathogenesis and progression of immunological response to viral infections in humans. Moreover, to test vaccines, anti-viral drugs and therapeutic agents, mouse models are fundamental for preclinical investigations. Human viruses, however, seldom infect mice due to differences in the cellular receptors used by the viruses for entry, as well as in the innate immune responses in mice and humans. In other words, a species barrier exists when using mouse models for investigating human viral infections. Developing transgenic (Tg) mice models expressing the human genes coding for viral entry receptors and knock-out (KO) mice models devoid of components involved in the innate immune response have, to some extent, overcome this barrier. Humanized mouse models are a third approach, developed by engrafting functional human cells and tissues into immunodeficient mice. They are becoming indispensable for analyzing human viral diseases since they nearly recapitulate the human disease. These mouse models also serve to test the efficacy of vaccines and antiviral agents. This review provides an update on the Tg, KO, and humanized mouse models that are used in studies investigating the pathogenesis of three important human-specific viruses, namely human immunodeficiency (HIV) virus 1, influenza, and dengue.

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Humanized Mouse Models for the Study of Periodontitis: An Opportunity to Elucidate Unresolved Aspects of Its Immunopathogenesis and Analyze New Immunotherapeutic Strategies

Frontiers in Immunology ◽

10.3389/fimmu.2021.663328 ◽

2021 ◽

Vol 12 ◽

Author(s):

Carolina Rojas ◽

Michelle P. García ◽

Alan F. Polanco ◽

Luis González-Osuna ◽

Alfredo Sierra-Cristancho ◽

...

Keyword(s):

Immune Response ◽

Animal Models ◽

Mouse Models ◽

Time Window ◽

Molecular Characteristics ◽

Specific Response ◽

Humanized Mouse ◽

Immunodeficient Mice ◽

Th17 Lymphocytes ◽

Humanized Mouse Models

Periodontitis is an oral inflammatory disease in which the polymicrobial synergy and dysbiosis of the subgingival microbiota trigger a deregulated host immune response, that leads to the breakdown of tooth-supporting tissues and finally tooth loss. Periodontitis is characterized by the increased pathogenic activity of T helper type 17 (Th17) lymphocytes and defective immunoregulation mediated by phenotypically unstable T regulatory (Treg), lymphocytes, incapable of resolving the bone-resorbing inflammatory milieu. In this context, the complexity of the immune response orchestrated against the microbial challenge during periodontitis has made the study of its pathogenesis and therapy difficult and limited. Indeed, the ethical limitations that accompany human studies can lead to an insufficient etiopathogenic understanding of the disease and consequently, biased treatment decision-making. Alternatively, animal models allow us to manage these difficulties and give us the opportunity to partially emulate the etiopathogenesis of periodontitis by inoculating periodontopathogenic bacteria or by placing bacteria-accumulating ligatures around the teeth; however, these models still have limited translational application in humans. Accordingly, humanized animal models are able to emulate human-like complex networks of immune responses by engrafting human cells or tissues into specific strains of immunodeficient mice. Their characteristics enable a viable time window for the study of the establishment of a specific human immune response pattern in an in vivo setting and could be exploited for a wider study of the etiopathogenesis and/or treatment of periodontitis. For instance, the antigen-specific response of human dendritic cells against the periodontopathogen Porphyromonas gingivalis favoring the Th17/Treg response has already been tested in humanized mice models. Hypothetically, the proper emulation of periodontal dysbiosis in a humanized animal could give insights into the subtle molecular characteristics of a human-like local and systemic immune response during periodontitis and support the design of novel immunotherapeutic strategies. Therefore, the aims of this review are: To elucidate how the microbiota-elicited immunopathogenesis of periodontitis can be potentially emulated in humanized mouse models, to highlight their advantages and limitations in comparison with the already available experimental periodontitis non-humanized animal models, and to discuss the potential translational application of using these models for periodontitis immunotherapeutics.

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Humanized Mouse Models for the Study of Infection and Pathogenesis of Human Viruses

Viruses ◽

10.3390/v10110643 ◽

2018 ◽

Vol 10 (11) ◽

pp. 643 ◽

Cited By ~ 5

Author(s):

Fritz Lai ◽

Qingfeng Chen

Keyword(s):

Immune Responses ◽

Mouse Models ◽

Viral Infections ◽

Life Cycles ◽

Human Immune System ◽

Humanized Mouse ◽

Human Immune ◽

Humanized Mouse Models ◽

Immunocompromised Mice

The evolution of infectious pathogens in humans proved to be a global health problem. Technological advancements over the last 50 years have allowed better means of identifying novel therapeutics to either prevent or combat these infectious diseases. The development of humanized mouse models offers a preclinical in vivo platform for further characterization of human viral infections and human immune responses triggered by these virus particles. Multiple strains of immunocompromised mice reconstituted with a human immune system and/or human hepatocytes are susceptible to infectious pathogens as evidenced by establishment of full viral life cycles in hope of investigating viral–host interactions observed in patients and discovering potential immunotherapies. This review highlights recent progress in utilizing humanized mice to decipher human specific immune responses against viral tropism.

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Perspectives on Non-BLT Humanized Mouse Models for Studying HIV Pathogenesis and Therapy

Viruses ◽

10.3390/v13050776 ◽

2021 ◽

Vol 13 (5) ◽

pp. 776

Author(s):

Kazutaka Terahara ◽

Ryutaro Iwabuchi ◽

Yasuko Tsunetsugu-Yokota

Keyword(s):

Mouse Models ◽

Humanized Mice ◽

Lymphoid Tissues ◽

Humanized Mouse ◽

Hiv Pathogenesis ◽

Hematopoietic Stem ◽

Critical Issues ◽

In Vivo Animal Models ◽

Humanized Mouse Models

A variety of humanized mice, which are reconstituted only with human hematopoietic stem cells (HSC) or with fetal thymus and HSCs, have been developed and widely utilized as in vivo animal models of HIV-1 infection. The models represent some aspects of HIV-mediated pathogenesis in humans and are useful for the evaluation of therapeutic regimens. However, there are several limitations in these models, including their incomplete immune responses and poor distribution of human cells to the secondary lymphoid tissues. These limitations are common in many humanized mouse models and are critical issues that need to be addressed. As distinct defects exist in each model, we need to be cautious about the experimental design and interpretation of the outcomes obtained using humanized mice. Considering this point, we mainly characterize the current conventional humanized mouse reconstituted only with HSCs and describe past achievements in this area, as well as the potential contributions of the humanized mouse models for the study of HIV pathogenesis and therapy. We also discuss the use of various technologies to solve the current problems. Humanized mice will contribute not only to the pre-clinical evaluation of anti-HIV regimens, but also to a deeper understanding of basic aspects of HIV biology.

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Humanized Mouse Models to Study Cell-Mediated Immune Responses to Liver-Stage Malaria Vaccines

Trends in Parasitology ◽

10.1016/j.pt.2015.06.008 ◽

2015 ◽

Vol 31 (11) ◽

pp. 583-594 ◽

Cited By ~ 15

Author(s):

Michael F. Good ◽

Michael T. Hawkes ◽

Stephanie K. Yanow

Keyword(s):

Immune Responses ◽

Mouse Models ◽

Humanized Mouse ◽

Liver Stage ◽

Malaria Vaccines ◽

Humanized Mouse Models

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The Future is NOW for Humanized Mouse Models

Humanized Mice for HIV Research ◽

10.1007/978-1-4939-1655-9_42 ◽

2014 ◽

pp. 531-534

Author(s):

J. Victor Garcia

Keyword(s):

Mouse Models ◽

Humanized Mouse ◽

The Future ◽

Humanized Mouse Models

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Generation of Novel Human Red Blood Cell-Bearing Humanized Mouse Models Based on C3-Deficient NOG Mice

Frontiers in Immunology ◽

10.3389/fimmu.2021.671648 ◽

2021 ◽

Vol 12 ◽

Author(s):

Takuya Yamaguchi ◽

Ikumi Katano ◽

Iyo Otsuka ◽

Ryoji Ito ◽

Misa Mochizuki ◽

...

Keyword(s):

Mouse Models ◽

Complement C3 ◽

Humanized Mouse ◽

Hematopoietic Stem ◽

Gm Csf ◽

Human Red Blood Cells ◽

Mouse Macrophages ◽

C3 Gene ◽

Humanized Mouse Models

Despite recent advances in immunodeficient mouse models bearing human red blood cells (hRBCs), the elimination of circulating hRBCs by residual innate immune systems remains a significant challenge. In this study, we evaluated the role of mouse complement C3 in the elimination of circulating hRBCs by developing a novel NOG substrain harboring a truncated version of the murine C3 gene (NOG-C3ΔMG2-3). Genetic C3 deletion prolonged the survival of transfused hRBCs in the circulation. Chemical depletion and functional impairment of mouse macrophages, using clodronate liposomes (Clo-lip) or gadolinium chloride (GdCl3), respectively, further extended the survival of hRBCs in NOG-C3ΔMG2-3 mice. Low GdCl3 toxicity allowed the establishment of hRBC-bearing mice, in which hRBCs survived for more than 4 weeks with transfusion once a week. In addition, erythropoiesis of human hematopoietic stem cells (hHSCs) was possible in NOG-C3ΔMG2-3/human GM-CSF-IL-3 transgenic mice with Clo-lip treatment. These findings indicate that mouse models harboring hRBCs can be achieved using NOG-C3ΔMG2-3 mice, which could facilitate studies of human diseases associated with RBCs.

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