Effects of lymphocyte profile on development of EBV-induced lymphoma subtypes in humanized mice

Lee, Eun Kyung; Joo, Eun Young; Song, Kwon‐Ho; Choi, Bomi; Kim, Miyoung; Kim, Seok-Hyung; Kim, Sung Joo; Kang, Myung-Soo

doi:10.1073/pnas.1407075112

Cited by 25 publications

(22 citation statements)

References 53 publications

(74 reference statements)

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“…Importantly, the BLTS humanized mouse model could enable the unraveling of the nexus between lymphoid tissue fibrosis and persistent immune abnormalities, including chronic inflammation, functional exhaustion of antiviral T cells, and limited immune reconstitution under conditions of robust ART-mediated HIV suppression. Additionally, human immune system-humanized mouse models have been employed for in vivo mechanistic studies for a myriad of human diseases, including cancer (51,52), viral infections (53)(54)(55)(56)(57)(58)(59)(60)(61)(62), and bacterial infections (63,64); thus, the BLTS humanized mouse model represents a potentially novel in vivo platform for biomedical research.…”

Section: Discussionmentioning

confidence: 99%

Human immunodeficiency virus infection induces lymphoid fibrosis in the BM-liver-thymus-spleen humanized mouse model

Samal¹,

Kelly²,

Na-Shatal³

et al. 2018

JCI Insight

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A major pathogenic feature associated with HIV infection is lymphoid fibrosis, which persists during antiretroviral therapy (ART). Lymphoid tissues play critical roles in the generation of antigen-specific immune response, and fibrosis disrupts the stromal network of lymphoid tissues, resulting in impaired immune cell trafficking and function, as well as immunodeficiency. Developing an animal model for investigating the impact of HIV infection-induced lymphoid tissue fibrosis on immunodeficiency and immune cell impairment is critical for therapeutics development and clinical translation. Said model will enable in vivo mechanistic studies, thus complementing the well-established surrogate model of SIV infection-induced lymphoid tissue fibrosis in macaques. We developed a potentially novel human immune system-humanized mouse model by coengrafting autologous fetal thymus, spleen, and liver organoids under the kidney capsule, along with i.v. injection of autologous fetal liver-derived hematopoietic stem cells, thus termed the BM-liver-thymus-spleen (BLTS) humanized mouse model. BLTS humanized mouse model supports development of human immune cells and human lymphoid organoids (human thymus and spleen organoids). HIV infection in BLTS humanized mice results in progressive fibrosis in human lymphoid tissues, which was associated with immunodeficiency in the lymphoid tissues, and lymphoid tissue fibrosis persists during ART, thus recapitulating clinical outcomes.

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Section: Discussionmentioning

confidence: 99%

Human immunodeficiency virus infection induces lymphoid fibrosis in the BM-liver-thymus-spleen humanized mouse model

Samal¹,

Kelly²,

Na-Shatal³

et al. 2018

JCI Insight

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“…Recently, Lee and others investigated the effects of lymphocyte profile on the development of EBV-induced lymphoma subtypes in humanized mice and found that a fraction of humanized mice in which T cells were predominantly reconstituted developed lymphomas of HL-like histology with EBV-infected cells of Hodgkin-Reed/Sternberg (HRS)-like morphology [48]. These HRS-like cells displayed the latency II pattern of EBV gene expression and expressed the HL markers, CD15 and CD30.…”

Section: Lpd/lymphoma Induced By Ebv Infection In Humanized Micementioning

confidence: 99%

Animal Models for Gammaherpesvirus Infections: Recent Development in the Analysis of Virus-Induced Pathogenesis

Fujiwara

Nakamura

2020

Pathogens

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Epstein–Barr virus (EBV) is involved in the pathogenesis of various lymphomas and carcinomas, whereas Kaposi’s sarcoma-associated herpesvirus (KSHV) participates in the pathogenesis of endothelial sarcoma and lymphomas. EBV and KSHV are responsible for 120,000 and 44,000 annual new cases of cancer, respectively. Despite this clinical importance, no chemotherapies or vaccines have been developed for virus-specific treatment and prevention of these viruses. Humans are the only natural host for both EBV and KSHV, and only a limited species of laboratory animals are susceptible to their experimental infection; this strict host tropism has hampered the development of their animal models and thereby impeded the study of therapeutic and prophylactic strategies. To overcome this difficulty, three main approaches have been used to develop animal models for human gammaherpesvirus infections. The first is experimental infection of laboratory animals with EBV or KSHV. New-world non-human primates (NHPs) and rabbits have been mainly used in this approach. The second is experimental infection of laboratory animals with their own inherent gammaherpesviruses. NHPs and mice have been mainly used here. The third, a recent trend, employs experimental infection of EBV or KSHV or both to immunodeficient mice reconstituted with human immune system components (humanized mice). This review will discuss how these three approaches have been used to reproduce human clinical conditions associated with gammaherpesviruses and to analyze the mechanisms of their pathogenesis.

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“…hSIS-humanized NSG mice and SRG rats provide a means of addressing several limitations in conventional rodents for modeling human skin biology/pathobiology and associated cutaneous immune responses, including microanatomy differences, susceptibility to human infectious agents and associated diseases, and cutaneous immune cell signaling. hSIShumanized NSG mouse and SRG rat models provide robust rodent models for in vivo mechanistic studies of a myriad of human diseases associated with the skin, including cancer 39,40 , viral infections [41][42][43][44][45][46][47][48][49][50] , bacterial infections 51,52 , etc. ; thus our hSIS-humanized rodent models represents a novel in vivo platform for biomedical research.…”

Section: Discussionmentioning

confidence: 99%

Development of humanized mouse and rat models with full-thickness human skin and autologous immune cells

Agarwal

Beatty

et al. 2020

Preprint

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The human skin is a major barrier for host defense against many human pathogens, with several pathogens directly targeting the skin for replication and disease. The skin is also the primary route of infection for a myriad of vector-borne diseases; thus cutaneous immune cells play a major role in modulating transmission for such infectious diseases. Several human pathogens that target the skin as a major route of infection are unable to infect traditional rodent models or recapitulate the pathogenesis in humans. It is well established that differences exist in human skin and immune cell biology compared to rodent models. Therefore, rodent (mouse and rat) models that incorporate human skin and immune cells would addressed the above discussed technical gap, and enable in vivo mechanistic studies of human host-skin pathogen interactions, and support the development of novel therapeutics. Here, we introduce the novel human Skin and Immune System (hSIS)-humanized NOD-scid IL2Rg null (NSG) mouse and Sprague-Dawley-Rag2 tm2hera Il2rg tm1hera (SRG) rat models, coengrafted with full-thickness human fetal skin, autologous fetal lymphoid tissues, and fetal liverderived hematopoietic stem cells. hSIS-humanized rodents support the development of adult-like, fullthickness human skin and human lymphoid tissues, and support human immune cell development.Furthermore, the engrafted human skin supports Methicillin-resistant Staphylococcus aureus infection, demonstrating the utility of these humanized rodent models in studying human disease.

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Effects of lymphocyte profile on development of EBV-induced lymphoma subtypes in humanized mice

Cited by 25 publications

References 53 publications

Human immunodeficiency virus infection induces lymphoid fibrosis in the BM-liver-thymus-spleen humanized mouse model

Human immunodeficiency virus infection induces lymphoid fibrosis in the BM-liver-thymus-spleen humanized mouse model

Animal Models for Gammaherpesvirus Infections: Recent Development in the Analysis of Virus-Induced Pathogenesis

Development of humanized mouse and rat models with full-thickness human skin and autologous immune cells

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