ArticlePLoS pathogens2011
Novel mouse xenograft models reveal a critical role of CD4+ T cells in the proliferation of EBV-infected T and NK cells.
Article in PLoS pathogens, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 53 citations in OpenAlex.
- JAK1/2 inhibitor ruxolitinib for the treatment of systemic chronic active Epstein-Barr virus disease: a phase 2 study.Blood neoplasia · 2025Trial
- Insights into oncovirus-driven tumor dynamics: a perspective from intravital imaging.Frontiers in cell and developmental biology · 2026Review
- Effects of venetoclax, a BCL2 inhibitor, in systemic chronic active Epstein-Barr virus disease.Scientific reports · 2025Article
- The pathophysiology of hemophagocytic lympho-histiocytosis (HLH) syndrome and insights from animal models.Clinical and experimental immunology · 2025Review
- Murine Models of Secondary Cytokine Storm Syndromes.Advances in experimental medicine and biology · 2024Review
- Article
- Increased expression of the TLR7/9 signaling pathways in chronic active EBV infection.Frontiers in pediatrics · 2022Article
- Antineoplastic and anti-inflammatory effects of bortezomib on systemic chronic active EBV infection.Blood advances · 2021Article
- Animal Models for Gammaherpesvirus Infections: Recent Development in the Analysis of Virus-Induced Pathogenesis.Pathogens (Basel, Switzerland) · 2020Review
- The face of CD4Annals of dermatology · 2019Article
- Dual Threat of Epstein-Barr Virus: an Autopsy Case Report of HIV-Positive Plasmablastic Lymphoma Complicating EBV-Associated Hemophagocytic Lymphohistiocytosis.Journal of clinical immunology · 2018Article
- An Efficient and Simple Method to Establish NK and T Cell Lines from Patients with Chronic Active Epstein-Barr Virus Infection.Journal of visualized experiments : JoVE · 2018Article
- Beta and Gamma Human Herpesviruses: Agonistic and Antagonistic Interactions with the Host Immune System.Frontiers in microbiology · 2017Review
- EBV induces persistent NF-κB activation and contributes to survival of EBV-positive neoplastic T- or NK-cells.PloS one · 2017Article
- A xenograft model of macrophage activation syndrome amenable to anti-CD33 and anti-IL-6R treatment.JCI insight · 2016Article
- Effects of lymphocyte profile on development of EBV-induced lymphoma subtypes in humanized mice.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Modeling EBV infection and pathogenesis in new-generation humanized mice.Experimental & molecular medicine · 2015Review
- EBV and human cancer.Experimental & molecular medicine · 2015Article
- Anti-tumor effects of suberoylanilide hydroxamic acid on Epstein-Barr virus-associated T cell and natural killer cell lymphoma.Cancer science · 2014Article
- Reproduction of epstein-barr virus infection and pathogenesis in humanized mice.Immune network · 2014Article
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Authors and funding
15 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Epstein-Barr virus (EBV), a ubiquitous B-lymphotropic herpesvirus, ectopically infects T or NK cells to cause severe diseases of unknown pathogenesis, including chronic active EBV infection (CAEBV) and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH). We developed xenograft models of CAEBV and EBV-HLH by transplanting patients' PBMC to immunodeficient mice of the NOD/Shi-scid/IL-2Rγ(null) strain. In these models, EBV-infected T, NK, or B cells proliferated systemically and reproduced histological characteristics of the two diseases. Analysis of the TCR repertoire expression revealed that identical predominant EBV-infected T-cell clones proliferated in patients and corresponding mice transplanted with their PBMC. Expression of the EBV nuclear antigen 1 (EBNA1), the latent membrane protein 1 (LMP1), and LMP2, but not EBNA2, in the engrafted cells is consistent with the latency II program of EBV gene expression known in CAEBV. High levels of human cytokines, including IL-8, IFN-γ, and RANTES, were detected in the peripheral blood of the model mice, mirroring hypercytokinemia characteristic to both CAEBV and EBV-HLH. Transplantation of individual immunophenotypic subsets isolated from patients' PBMC as well as that of various combinations of these subsets revealed a critical role of CD4+ T cells in the engraftment of EBV-infected T and NK cells. In accordance with this finding, in vivo depletion of CD4+ T cells by the administration of the OKT4 antibody following transplantation of PBMC prevented the engraftment of EBV-infected T and NK cells. This is the first report of animal models of CAEBV and EBV-HLH that are expected to be useful tools in the development of novel therapeutic strategies for the treatment of the diseases.
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