Humanized Mice as Unique Tools for Human-Specific Studies

Yong, Kylie Su Mei; Her, Zhisheng; Chen, Yi‐Ping Phoebe

doi:10.1007/s00005-018-0506-x

Cited by 81 publications

(73 citation statements)

References 192 publications

(313 reference statements)

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“…However, the utility of a given model for studying RIHD is dependent on the method and type of immune engraftment. For example, CB-17-scid, NOD-scid, and NOG mice are highly suitable for oncological studies but have a low tolerance to radiation [190]. In studying normal tissue radiation toxicities in these mouse models, radiation doses may have to be reduced to obtain the same normal tissue pathologies as in common wild-type mice.…”

Section: Radiation Therapy and The Immune Responsementioning

confidence: 99%

Advances in Preclinical Research Models of Radiation-Induced Cardiac Toxicity

Schlaak

SenthilKumar

Boerma

et al. 2020

Cancers

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Radiation therapy (RT) is an important component of cancer therapy, with >50% of cancer patients receiving RT. As the number of cancer survivors increases, the short-and long-term side effects of cancer therapy are of growing concern. Side effects of RT for thoracic tumors, notably cardiac and pulmonary toxicities, can cause morbidity and mortality in long-term cancer survivors. An understanding of the biological pathways and mechanisms involved in normal tissue toxicity from RT will improve future cancer treatments by reducing the risk of long-term side effects. Many of these mechanistic studies are performed in animal models of radiation exposure. In this area of research, the use of small animal image-guided RT with treatment planning systems that allow more accurate dose determination has the potential to revolutionize knowledge of clinically relevant tumor and normal tissue radiobiology. However, there are still a number of challenges to overcome to optimize such radiation delivery, including dose verification and calibration, determination of doses received by adjacent normal tissues that can affect outcomes, and motion management and identifying variation in doses due to animal heterogeneity. In addition, recent studies have begun to determine how animal strain and sex affect normal tissue radiation injuries. This review article discusses the known and potential benefits and caveats of newer technologies and methods used for small animal radiation delivery, as well as how the choice of animal models, including variables such as species, strain, and age, can alter the severity of cardiac radiation toxicities and impact their clinical relevance.

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Section: Radiation Therapy and The Immune Responsementioning

confidence: 99%

Advances in Preclinical Research Models of Radiation-Induced Cardiac Toxicity

Schlaak

SenthilKumar

Boerma

et al. 2020

Cancers

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“…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 . Two previously reported transgenic humanized MC expressing mouse strains have both been used to investigate human MC responses to IgE stimulation . In this regard, the findings of Ito et al .…”

Section: Discussionmentioning

confidence: 87%

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

Mencarelli

Gunawan

Yong

et al. 2020

Journal of Leukocyte Biology

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Recently a G-protein-coupled receptor, MAS Related GPR Family Member X2 (MRGPRX2), was identified as a specific receptor on human mast cells responsible for IgE independent adverse drug reactions (ADR). Although a murine homologue, Mrgprb2, has been identified for this receptor, its affinity for many ADR-causing drugs is poor making it difficult to undertake in vivo studies to examine mechanisms of ADR and to develop therapeutic strategies. Here, we have created humanized mice capable of generating MRGPRX2-expressing human MCs allowing for the study of MRGPRX2 MCs-mediated ADR in vitro as well as in vivo. Humanized mice were generated by hydrodynamic-injection of plasmids expressing human GM-CSF and IL-3 into NOD-scid IL2R-−/− strain of mice that had been transplanted with human hematopoietic stem cells. These GM/IL-3 humice expressed high numbers of tissue human MCs but the MRGPRX2 receptor expressed in MCs were limited to few body sites including the skin. Importantly, large numbers of MRGPRX2expressing human MCs could be cultured from the bone marrow of GM/IL-3 humice revealing these mice to be an important source of human MCs for in vitro studies of MRGPRX2-related MCs activities. When GM/IL-3 humice were exposed to known ADR causing contrast agents (meglumine and gadobutrol), the humice were found to experience anaphylaxis analogous to the clinical situation. Thus, GM/IL-3 humice represent a valuable model for investigating in vivo interactions of ADR-causing drugs and human MCs and their sequelae, and these mice are also a source of human MRGPRX2-expressing MCs for in vitro studies. K E Y W O R D Scontrast agents, mast cells, MRGPRX2 receptor, non-immune adverse drug reactions, pseudoallergy Abbreviations: ADR, adverse drug reactions; CB, cord blood; HSCs, hematopoietic stem cells; HSPCs, hematopoietic stem and progenitor cells; Hu-CB, human cord blood; mBM-MCs, mouse bone marrow cultured MCs; MCs, mast cells; MRGPRX2, MAS-related GPR family member X2; NSAIDs, nonsteroidal anti-inflammatory drugs; NSG, NOD-scid IL2R −/− /NOD scid gamma; SC, subcutaneously.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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“…One approach to studying this involves the use of humanized mouse models . Humanized mice (HuMice) are immunodeficient mice that lack endogenous murine immune cells but are engrafted with human stem cells to generate a functional human immune system . Over the last several decades, more advanced HuMice have been introduced using the most immunodeficient mouse strain NOD scid IL2Rγc −/− (“NSG”) to allow for optimal engraftment of human cells.…”

Section: Introductionmentioning

confidence: 99%

Rejection of xenogeneic porcine islets in humanized mice is characterized by graft-infiltrating Th17 cells and activated B cells

Lee

Dangi

Shah³

et al. 2020

American Journal of Transplantation

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Xenogeneic porcine islet transplantation is a promising potential therapy for type 1 diabetes (T1D). Understanding human immune responses against porcine islets is crucial for the design of optimal immunomodulatory regimens for effective control of xenogeneic rejection of porcine islets in humans. Humanized mice are a valuable tool for studying human immune responses and therefore present an attractive alternative to human subject research. Here, by using a pig‐to‐humanized mouse model of xenogeneic islet transplantation, we described the human immune response to transplanted porcine islets, a process characterized by dense islet xenograft infiltration of human CD45+ cells comprising activated human B cells, CD4+CD44+IL‐17+ Th17 cells, and CD68+ macrophages. In addition, we tested an experimental immunomodulatory regimen in promoting long‐term islet xenograft survival, a triple therapy consisting of donor splenocytes treated with ethylcarbodiimide (ECDI‐SP), and peri‐transplant rituximab and rapamycin. We observed that the triple therapy effectively inhibited graft infiltration of T and B cells as well as macrophages, promoted transitional B cells both in the periphery and in the islet xenografts, and provided a superior islet xenograft protection. Our study therefore indicates an advantage of donor ECDI‐SP treatment in controlling human immune cells in promoting long‐term islet xenograft survival.

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Humanized Mice as Unique Tools for Human-Specific Studies

Cited by 81 publications

References 192 publications

Advances in Preclinical Research Models of Radiation-Induced Cardiac Toxicity

Advances in Preclinical Research Models of Radiation-Induced Cardiac Toxicity

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

Rejection of xenogeneic porcine islets in humanized mice is characterized by graft-infiltrating Th17 cells and activated B cells

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