scholarly journals Enterovirus A71 Infection Activates Human Immune Responses and Induces Pathological Changes in Humanized Mice

2018 ◽  
Vol 93 (3) ◽  
Author(s):  
Yanyan Ke ◽  
Wai Nam Liu ◽  
Zhisheng Her ◽  
Min Liu ◽  
Sue Yee Tan ◽  
...  
Keyword(s):  
Immune Responses ◽  
Humanized Mice ◽  
Human Immune System ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Drug Candidates ◽  
Cell Responses ◽  
Human T Cell ◽  
Enterovirus A71 ◽  
Human Immune

ABSTRACT Since the discovery of enterovirus A71 (EV-A71) half a century ago, it has been recognized as the cause of large-scale outbreaks of hand-foot-and-mouth disease worldwide, particularly in the Asia-Pacific region, causing great concern for public health and economic burdens. Detailed mechanisms on the modulation of immune responses after EV-A71 infection have not been fully known, and the lack of appropriate models hinders the development of promising vaccines and drugs. In the present study, NOD-scid IL2Rγ−/− (NSG) mice with a human immune system (humanized mice) at the age of 4 weeks were found to be susceptible to a human isolate of EV-A71 infection. After infection, humanized mice displayed limb weakness, which is similar to the clinical features found in some of the EV-A71-infected patients. Histopathological examination indicated the presence of vacuolation, gliosis, or meningomyelitis in brain stem and spinal cord, which were accompanied by high viral loads detected in these organs. The numbers of activated human CD4+ and CD8+ T cells were upregulated after EV-A71 infection, and EV-A71-specific human T cell responses were found. Furthermore, the secretion of several proinflammatory cytokines, such as human gamma interferon (IFN-γ), interleukin-8 (IL-8), and IL-17A, was elevated in the EV-A71-infected humanized mice. Taken together, our results suggested that the humanized mouse model permits insights into the human immune responses and the pathogenesis of EV-A71 infection, which may provide a platform for the evaluation of anti-EV-A71 drug candidates in the future. IMPORTANCE Despite causing self-limited hand-food-and-mouth disease in younger children, EV-A71 is consistently associated with severe forms of neurological complications and pulmonary edema. Nevertheless, only limited vaccines and drugs have been developed over the years, which is possibly due to a lack of models that can more accurately recapitulate human specificity, since human is the only natural host for wild-type EV-A71 infection. Our humanized mouse model not only mimics histological symptoms in patients but also allows us to investigate the function of the human immune system during infection. It was found that human T cell responses were activated, accompanied by an increase in the production of proinflammatory cytokines in EV-A71-infected humanized mice, which might contribute to the exacerbation of disease pathogenesis. Collectively, this model allows us to delineate the modulation of human immune responses during EV-A71 infection and may provide a platform to evaluate anti-EV-A71 drug candidates in the future.

scholarly journals Nef dimerization defect abrogates HIV viremia and associated immune dysregulation in the Bone Marrow-Liver-Thymus-Spleen (BLTS) humanized mouse model

2021 ◽  
Author(s):  
Shivkumar Biradar ◽  
Yash Agarwal ◽  
Antu Das ◽  
Sherry T. Shu ◽  
Jasmine Samal ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mouse Model ◽  
Immune Responses ◽  
Immune Cells ◽  
Immune Dysregulation ◽  
Lymphoid Tissues ◽  
Human Immune System ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Human Immune

AbstractLoss of function mutations in the human immunodeficiency virus (HIV) negative factor (Nef) gene are associated with reduced viremia, robust T cell immune responses, and delayed acquired immunodeficiency syndrome (AIDS) progression in humans. In vitro studies have shown that mutations in the Nef dimerization interface significantly attenuate viral replication and impair host defense. However, in vivo, mechanistic studies on the role of Nef dimerization in HIV infection are lacking. Humanized rodents with human immune cells are robust platforms for investigating the interactions between HIV and the human immune system. The bone marrow-liver-thymus-spleen (BLTS) humanized mouse model carries human immune cells and lymphoid tissues that facilitate anti-viral immune responses. Here, we employed the BLTS-humanized mouse model to demonstrate that preventing Nef dimerization abrogates HIV viremia and the associated immune dysregulation. This suggests that Nef dimerization may be a therapeutic target for future HIV cure strategies.

scholarly journals P06.07 In vivo studies of immunomodulatory a-CTLA-4 antibody in a humanized mouse model

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A22.1-A22
Author(s):  
C Reitinger ◽  
F Nimmerjahn
Keyword(s):  
Immune System ◽  
Mouse Model ◽  
Cancer Immunotherapy ◽  
Model Systems ◽  
Checkpoint Control ◽  
Human Immune System ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Human Immune

BackgroundRecent findings in cancer immunotherapy have reinforced the hypothesis that the immune system is able to control most cancers. Immunomodulatory antibodies can enhance immune responses, having the potential to generate anti-cancer immunity.1–4Materials and MethodsMost current studies addressing this question are performed in murine mouse model systems or use in vitro culture systems, which do not reflect the human in vivo situation, potentially leading to results that cannot be fully translated into human cancer therapy. Therefore, it is necessary to establish a new mouse model, which allows the study of cancer immunotherapy in the context of a human immune system. We focused on the establishment of a humanized mouse model, in which different immunomodulatory antibodies can be tested in the presence of a human immune system.ResultsFirst experiments concerning the suitability to test immunomodulatory antibodies in the humanized mouse model, revealed that effects of checkpoint-control antibody a-CTLA-4 were similar to the effects seen in patients of clinical studies. To analyse the anti-tumor activities of immunomodulatory antibodies in vivo we are establishing a human melanoma-like tumor model in humanized mice.ConclusionsThis enables us to test the efficacy of immunomodulatory agonistic antibodies (such as CP-870,893) and checkpoint control antibodies (such as anti-CTLA-4) in eliminating a melanoma-like tumor. Furthermore, parameters like tumor infiltrating human cells und cytokine/chemokine production can be analysed.ReferencesSchuster M, Nechansky A, Loibner H. Cancer immunotherapy. Biotechnol J 2006;1:138–147.Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature rev 2011;480:480–489.Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Annals of Oncology 2012;23:vii6–vii9.Langer LF, Clay TM, Morse MA. Update on anti-CTLA-4 in clinical trials. Expert Opin Biol Ther 2007;8:1245–1256.Disclosure InformationC. Reitinger: None. F. Nimmerjahn: None.

scholarly journals Generation of a humanized mouse model with both human immune system and liver cells to model hepatitis C virus infection and liver immunopathogenesis

2012 ◽  
Vol 7 (9) ◽  
pp. 1608-1617 ◽  
Author(s):  
Moses T Bility ◽  
Liguo Zhang ◽  
Michael L Washburn ◽  
T Anthony Curtis ◽  
Grigoriy I Kovalev ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Immune System ◽  
Hepatitis C ◽  
Virus Infection ◽  
Mouse Model ◽  
Hepatitis C Virus Infection ◽  
Human Immune System ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Human Immune

scholarly journals A Human-Immune-System (HIS) humanized mouse model (DRAGA: HLA-A2. HLA-DR4. Rag1 KO.IL-2Rγc KO. NOD) for COVID-19

2021 ◽  
Author(s):  
Teodor-Doru Brumeanu ◽  
Pooja Vir ◽  
Ahmad Faisal Karim ◽  
Swagata Kar ◽  
Dalia Benetiene ◽  
...  
Keyword(s):  
Immune System ◽  
T Cell ◽  
Mouse Model ◽  
Human Model ◽  
Human Immune System ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Human Cord Blood ◽  
Hematopoietic Stem ◽  
Human Immune

Abstract We report the first Human Immune System (HIS)-humanized mouse model (“DRAGA”: HLA-A2.HLA-DR4.Rag1KO.IL-2RgcKO.NOD) for COVID-19 research. This mouse is reconstituted with human cord blood-derived, HLA-matched hematopoietic stem cells. It engrafts human epi/endothelial cells expressing the human ACE2 receptor for SARS-CoV-2 and TMPRSS2 serine protease co-localized on lung epithelia. HIS-DRAGA mice sustained SARS-CoV-2 infection, showing deteriorated clinical condition, replicating virus in the lungs, and human-like lung immunopathology including T-cell infiltrates, microthrombi and pulmonary sequelae. Among T-cell infiltrates, lung-resident (CD103+) CD8+ T cells were sequestered in epithelial (CD326+) lung niches and secreted granzyme B and perforin, indicating cytotoxic potential. Infected mice also developed antibodies against the SARS-CoV-2 viral proteins. Hence, HIS-DRAGA mice showed unique advantages as a surrogate in vivo human model for studying SARS-CoV-2 immunopathology and for testing the safety and efficacy of candidate vaccines and therapeutics.

scholarly journals A Human-Immune-System (HIS) humanized mouse model for COVID-19 research (DRAGA: HLA-A2.HLA-DR4.Rag1KO.IL-2Rγc KO.NOD)

2020 ◽  
Author(s):  
Teodor-Doru Brumeanu ◽  
Pooja Vir ◽  
Ahmad Faisal Karim ◽  
Swagata Kar ◽  
Kevin K. Chung ◽  
...  
Keyword(s):  
Immune System ◽  
T Cell ◽  
Mouse Model ◽  
Human Model ◽  
Human Immune System ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Hematopoietic Stem ◽  
Human Immune

We report the first Human Immune System (HIS)-humanized mouse model (DRAGA: HLA-A2.HLA-DR4.Rag1KO.IL-2RgammacKO.NOD) for SARS-CoV-2 infection and COVID-19 research. This mouse is reconstituted with HLA-matched human hematopoietic stem cells from cord blood, thereby avoiding use of fetal tissue. It engrafts human epi/endothelial cells expressing the human ACE2 receptor for SARS-CoV-2 and the TMPRSS2 serine protease, which co-localize on lung epithelia. HIS-DRAGA mice sustained SARS-CoV-2 infection, showing abrupt weight loss, ruffed fur, hunched back and reduced mobility. Infected mice developed human-like lung immunopathology including T-cell infiltrates, microthrombi, hemorrhage, and pulmonary sequelae. Among T-cell infiltrates, lung-resident (CD103+)CD8+ T cells were sequestered in epithelial (CD326+) lung niches and secreted granzyme B and perforin, indicating cytotoxic potential. Infected mice developed antibodies against the SARS-CoV-2 S protein. Hence, HIS-DRAGA mice show unique advantages as a surrogate in vivo human model for studying SARS-CoV-2 immunopathology and for testing the safety and efficacy of candidate vaccines and therapeutics.

scholarly journals Scrutiny of human lung infection by SARS-CoV-2 and associated human immune responses in humanized mice

2021 ◽  
Author(s):  
Zheng Hu ◽  
Renren Sun ◽  
Zongzheng Zhao ◽  
Cong Fu ◽  
Yixin Wang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Cell ◽  
Human Lung ◽  
Defense Responses ◽  
Humanized Mice ◽  
In Vivo Model ◽  
Bodyweight Loss ◽  
Human Immune System ◽  
Live Virus ◽  
Human Immune

There is an urgent need for animal models of COVID-19 to study immunopathogenesis and test therapeutic intervenes. In this study we showed that NSG mice engrafted with human lung (HL) tissue (NSG-L) could be infected efficiently by SARS-CoV-2, and that live virus capable of infecting Vero cells was found in the HL grafts and multiple organs from infected NSG-L mice. RNA-seq examination identified a series of differentially expressed genes, which are enriched in viral defense responses, chemotaxis, interferon stimulation, and pulmonary fibrosis between HL grafts from infected and control NSG-L mice. Furthermore, when infecting humanized mice with human immune system (HIS) and autologous HL grafts (HISL mice), the mice had bodyweight loss and hemorrhage and immune cell infiltration in HL grafts, which were not observed in immunodeficient NSG-L mice, indicating the development of anti-viral immune responses in these mice. In support of this possibility, the infected HISL mice showed bodyweight recovery and lack of detectable live virus at the later time. These results demonstrate that NSG-L and HISL mice are susceptible to SARS-CoV-2 infection, offering a useful in vivo model for studying SARS-CoV-2 infection and the associated immune response and immunopathology, and testing anti-SARS-CoV-2 therapies.

scholarly journals Functional Human CD141+ Dendritic Cells in Human Immune System Mice

2019 ◽  
Vol 221 (2) ◽  
pp. 201-213 ◽  
Author(s):  
Jordana G A Coelho-Dos-Reis ◽  
Ryota Funakoshi ◽  
Jing Huang ◽  
Felipe Valença Pereira ◽  
Sho Iketani ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune System ◽  
Mouse Model ◽  
Human Immune System ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Hematopoietic Stem ◽  
Virus Serotype ◽  
Human Immune

Abstract Background For the purpose of studying functional human dendritic cells (DCs) in a humanized mouse model that mimics the human immune system (HIS), a model referred to as HIS mice was established. Methods Human immune system mice were made by engrafting NOD/SCID/IL2Rgammanull (NSG) mice with human hematopoietic stem cells (HSCs) following the transduction of genes encoding human cytokines and human leukocyte antigen (HLA)-A2.1 by adeno-associated virus serotype 9 (AAV9) vectors. Results Our results indicate that human DC subsets, such as CD141+CD11c+ and CD1c+CD11c+ myeloid DCs, distribute throughout several organs in HIS mice including blood, bone marrow, spleen, and draining lymph nodes. The CD141+CD11c+ and CD1c+CD11c+ human DCs isolated from HIS mice immunized with adenoviruses expressing malaria/human immunodeficiency virus (HIV) epitopes were able to induce the proliferation of malaria/HIV epitopes-specific human CD8+ T cells in vitro. Upregulation of CD1c was also observed in human CD141+ DCs 1 day after immunization with the adenovirus-based vaccines. Conclusions Establishment of such a humanized mouse model that mounts functional human DCs enables preclinical assessment of the immunogenicity of human vaccines in vivo.

scholarly journals Nef Dimerization Defect Abrogates HIV Viremia and Associated Immune Dysregulation in the Bone Marrow-Liver-Thymus-Spleen (BLTS) Humanized Mouse Model.

2021 ◽  
Author(s):  
Shivkumar Biradar ◽  
Yash Agarwal ◽  
Antu Das ◽  
Sherry T. Shu ◽  
Jasmine Samal ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Antiretroviral Therapy ◽  
Mouse Model ◽  
Immune Responses ◽  
Immune Cells ◽  
Therapeutic Target ◽  
Immune Dysregulation ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Human Immune

Abstract BackgroundLoss of function mutations in the human immunodeficiency virus (HIV) negative factor (nef) gene are associated with reduced viremia, robust T cell immune responses, and delayed acquired immunodeficiency syndrome (AIDS) progression in humans. Importantly, Nef persists in antiretroviral therapy-treated chronic HIV-infected individuals. In vitro studies have shown that mutations in the Nef dimerization interface significantly attenuate viral replication and impair host defense. However, in vivo, mechanistic studies on the role of Nef dimerization in HIV infection are lacking. Humanized rodents with human immune cells are robust platforms for investigating the interactions between HIV and the human immune system. The bone marrow-liver-thymus-spleen (BLTS) humanized mouse model carries human immune cells and lymphoid tissues that facilitate anti-viral immune responses. ResultsHere, we demonstrate that nef deletion abrogates HIV viremia and HIV-induced immune dysregulation in the BLTS-humanized mouse model. Furthermore, we demonstrate that preventing Nef dimerization abrogates HIV viremia and HIV-induced immune dysregulation in the BLTS-humanized mouse model. We also demonstrate that viremic control of HIV carrying deletion or dimerization defects in nef is associated with robust antiviral innate immune signaling, T helper 1 (Th1) signaling, and reduced expression of Programmed cell death protein 1 (PD1) on T cells.ConclusionsOur results suggest that Nef dimerization may be a therapeutic target for adjuvants in immune-mediated HIV cure strategies. Furthermore, Nef dimerization may be a therapeutic target for ameliorating the residual immune dysregulation in antiretroviral therapy-treated chronic HIV-infected individuals.

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

Viruses ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 643 ◽  
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.

scholarly journals Recent Advances in Allergy Research Using Humanized Mice

2019 ◽  
Vol 20 (11) ◽  
pp. 2740 ◽  
Author(s):  
Ryoji Ito ◽  
Shuichiro Maruoka ◽  
Yasuhiro Gon ◽  
Ikumi Katano ◽  
Takeshi Takahashi ◽  
...  
Keyword(s):  
Immune Cells ◽  
Allergic Diseases ◽  
Humanized Mice ◽  
Efficacy And Safety ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Industrial Countries ◽  
Preclinical Evaluation ◽  
Genetic Technologies ◽  
Human Immune

The prevalence rates of allergic diseases are increasing worldwide, particularly in industrial countries. To date, many mouse models have been generated for allergy research; studies conducted using these models have suggested the importance of cross-talk between immune cells and tissue-resident non-immune cells in the onset of allergic diseases. However, there are several differences between the immune systems of rodents and humans, and human studies are limited. Thus, mice reconstituted with human immune cells are a novel tool for the preclinical evaluation of the efficacy and safety of developing drugs. Genetic technologies for generating humanized mice have improved markedly in recent years. In this review, we will discuss recent progress in allergy research using humanized mice and introduce our recent humanized mouse model of airway inflammation in human immune cells.

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