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

ABSTRACTIt is still unclear if immune responses will compromise the large scale utilization of cell therapies derived from human induced pluripotent stem cells (hiPSCs). To answer this question, we used humanized mouse models and evaluated the engraftment in skeletal muscle of myoblasts derived either directly from a muscle biopsy or differentiated from hiPSCs or fibroblasts. Our results showed that while allogeneic grafts were rejected, engraftment of autologous cells was tolerated, indicating reprogramming and differentiation procedures are not immunogenic. We also demonstrated that hiPSC-derived myogenic progenitors, in opposition to hiPSCs, are not targeted by natural killer (NK) cells both in vitro and in vivo. Yet, adoptive transfer of NK cells can prevent the formation of hiPSC-derived teratoma. Overall, our findings suggest that hiPSC-derived muscular therapies will be tolerated in presence of a competent human immune system and highlight the risk of forming a teratoma if using partially differentiated autologous human cells.HighlightshiPSC-derived myofibers are tolerated in autologous humanized mouse modelsInfiltration of autologous T cells is not predictive of successful skeletal muscle engraftmentAdoptive transfer of NK cells prevents the formation of hiPSCs derived teratomasNK cells are unable to reject established teratomas

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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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Establishment of Human Leukocyte Antigen-Mismatched Immune Responses after Transplantation of Human Liver Bud in Humanized Mouse Models

Cells ◽

10.3390/cells10020476 ◽

2021 ◽

Vol 10 (2) ◽

pp. 476

Author(s):

Akihiro Mori ◽

Soichiro Murata ◽

Nao Tashiro ◽

Tomomi Tadokoro ◽

Satoshi Okamoto ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Human Leukocyte Antigen ◽

Mouse Models ◽

Human Leukocyte ◽

Tissue Transplantation ◽

Humanized Mouse ◽

Hematopoietic Stem ◽

Leukocyte Antigen ◽

Humanized Mouse Models

Humanized mouse models have contributed significantly to human immunology research. In transplant immunity, human immune cell responses to donor grafts have not been reproduced in a humanized animal model. To elicit human T-cell immune responses, we generated immune-compromised nonobese diabetic/Shi-scid, IL-2RγKO Jic (NOG) with a homozygous expression of human leukocyte antigen (HLA) class I heavy chain (NOG-HLA-A2Tg) mice. After the transplantation of HLA-A2 human hematopoietic stem cells into NOG-HLA-A2Tg, we succeeded in achieving alloimmune responses after the HLA-mismatched human-induced pluripotent stem cell (hiPSC)-derived liver-like tissue transplantation. This immune response was inhibited by administering tacrolimus. In this model, we reproduced allograft rejection after the human iPSC-derived liver-like tissue transplantation. Human tissue transplantation on the humanized mouse liver surface is a good model that can predict T-cell-mediated cellular rejection that may occur when organ transplantation is performed.

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Modeling HBV infections and immune responses in humanized mouse models

Journal of Hepatology ◽

10.1016/s0168-8278(18)31851-8 ◽

2018 ◽

Vol 68 ◽

pp. S790

Author(s):

M. Dusseaux ◽

G. Masse-Ranson ◽

S. Darche ◽

J. Ahodantin ◽

Y. Li ◽

...

Keyword(s):

Immune Responses ◽

Mouse Models ◽

Humanized Mouse ◽

Humanized Mouse Models

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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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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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