Priming of protective T cell responses against virus-induced tumors in mice with human immune system components

Strowig, Till; Gurer, Cagan; Ploß, Alexander; Liu, Yifang; Arrey, Frida; Sashihara, Junji; Koo, Gloria C.; Rice, Charles M.; Young, James W.; Chadburn, Amy; Cohen, Jeffrey I.; Münz, Christian

doi:10.1084/jem.20081720

Cited by 272 publications

(409 citation statements)

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“…Both latent and lytic EBV antigen expression can be observed in infected HIS mice (Strowig et al, 2009;Chijioke et al, 2013;Tsai et al, 2013). Depending on the dose of EBV, it is possible to generate asymptomatic persistent infection or acute infectious mononucleosis-like symptoms, as well as lymphoproliferative disease in HIS mice (Yajima et al, 2008).…”

Section: Programs Of Ebv Infection In His Micementioning

confidence: 99%

“…Depending on the dose of EBV, it is possible to generate asymptomatic persistent infection or acute infectious mononucleosis-like symptoms, as well as lymphoproliferative disease in HIS mice (Yajima et al, 2008). Latency III expressing cells can be found in all of these instances, as assessed by immunohistochemistry and in situ hybridization for EBV-encoded RNAs (EBERs), EBNA1, EBNA2, and LMP1 (Cocco et al, 2008;Strowig et al, 2009). However, it has been suggested that asymptomatic persistent infection without the massive lymphocyte expansion of infectious mononucleosis can also result in lower latency stages (Islas-Ohlmayer et al, 2004;Cocco et al, 2008;Ma et al, 2011).…”

Section: Programs Of Ebv Infection In His Micementioning

confidence: 99%

“…With respect to lytic replication, latent EBV-infected B cells far outnumber lytic EBV antigen expressing cells in HIS mice that have been infected with the B95-8 EBV strain, a clinical isolate from an American infectious mononucleosis patient (Miller and Lipman, 1973;Strowig et al, 2009;Chijioke et al, 2013). In these rare, lytically EBV replicating cells however, both early and late lytic antigen expression can be found (Chijioke et al, 2013).…”

Section: Programs Of Ebv Infection In His Micementioning

confidence: 99%

“…The development of certain EBV-associated diseases can be studied in HIS mice. Infection with a high dose of EBV wild-type strain B95-8 leads to lymphoproliferative disease and tumor generation (Yajima et al, 2008;Strowig et al, 2009). B cells primarily harbor the virus and can be purified from EBV-infected HIS mice and cultured in vitro as immortalized lymphoblastoid cell lines (LCLs).…”

Section: Ebv-associated Diseases In His Micementioning

confidence: 99%

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Animal models of Epstein Barr virus infection

Chatterjee

Leung

Münz

2014

Journal of Immunological Methods

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Epstein Barr virus (EBV) was the first human tumor virus to be identified. Despite 50years of research on this oncogenic virus, no therapeutic or prophylactic vaccine is available against this pathogen. In part, the development of such a vaccine is hampered by the lack of in vivo models for EBV infection and immune control. However, with the advent of mice with reconstituted human immune system components (HIS mice), certain aspects of EBV associated diseases and immune responses can be modeled in vivo. In this review, we will discuss the insights that can be gained from these experiments, and how immune system components can be manipulated to interrogate their function during EBV infection. Finally, we will compare EBV immunobiology in HIS mice to infection by EBV-related viruses in monkeys, and we will outline the strengths and weaknesses of these two in vivo models of EBV infection. Both of these models show great promise as a platform for preclinical EBV vaccine testing. AbstractEpstein Barr virus (EBV) was the first human tumor virus to be identified. Despite 50 years of research on this oncogenic virus, no therapeutic or prophylactic vaccine is available against this pathogen. In part, the development of such a vaccine is hampered by the lack of in vivo models for EBV infection and immune control. However, with the advent of mice with reconstituted human immune system components (HIS mice), certain aspects of EBV associated diseases and immune responses can be modeled in vivo. In this review, we will discuss the insights that can be gained from these experiments, and how immune system components can be manipulated to interrogate their function during EBV infection. Finally, we will compare EBV immunobiology in HIS mice to infection by EBV-related viruses in monkeys, and we will outline the strengths and weaknesses of these two in vivo models of EBV infection. Both of these models show great promise as a platform for preclinical EBV vaccine testing. Chatterjee et al. 3

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Section: Programs Of Ebv Infection In His Micementioning

confidence: 99%

Section: Programs Of Ebv Infection In His Micementioning

confidence: 99%

Section: Programs Of Ebv Infection In His Micementioning

confidence: 99%

Section: Ebv-associated Diseases In His Micementioning

confidence: 99%

See 2 more Smart Citations

Animal models of Epstein Barr virus infection

Chatterjee

Leung

Münz

2014

Journal of Immunological Methods

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“…Primary infection as well as subsequent reactivation of the virus of EBV-infected B cells are tightly controlled by both CD8 1 and CD4 1 T cells [1,12]. Therefore, immunosuppressive therapy [13], hereditary immunodeficiencies [14] or immunocompromising HIV-infection [15] may lead to uncontrolled EBV reactivation and disease.…”

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confidence: 99%

Human peripheral blood and bone marrow Epstein–Barr virus‐specific T‐cell repertoire in latent infection reveals distinct memory T‐cell subsets

Guerreiro

Letsch

et al. 2010

Eur J Immunol

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EBV infection leads to life-long viral persistence. Although EBV infection can result in chronic disease and malignant transformation, most carriers remain disease-free as a result of effective control by T cells. EBV-specific IFN-c-producing T cells could be demonstrated in acute and chronic infection as well as during latency. Recent studies, however, provide evidence that assessing IFN-c alone is insufficient to assess the quantity and quality of a T-cell response. Using overlapping peptide pools of latent EBV nuclear antigen 1 and lytic BZLF-1 protein and multicolor flow cytometry, we demonstrate that the majority of ex vivo EBV-reactive T cells in healthy virus carriers are indeed IL-2-and/or TNF-producing memory cells, the latter being significantly more frequent in BM. After in vitro expansion, a substantial number of EBV-specific CD4 1 and CD8 1 T cells retained a CC-chemokine receptor 7 (CCR7)-positive memory phenotype. Based on their cytokine profiles, six different EBV-specific T-cell subsets could be distinguished with TNF-single or TNF/IL-2-double producing cells expressing the highest CCR7 levels resembling earlydifferentiated memory T cells. Our study delineates the memory T-cell profile of a protective immune response and provides a basis for analyzing T-cell responses in EBVassociated diseases.Key words: BM . EBV . Immune monitoring . Multifunctional T cells . T-cell memory IntroductionEBV is a human gamma herpesvirus that is widespread in all human populations. Following oral transmission, EBV replicates in the oropharyngeal epithelial cells and infects mucosal B cells, leading to a life-long persistence in the memory B-cell pool [1,2]. The primary infection occurs usually during childhood and is often asymptomatic; however, infection is manifested as acute infectious mononucleosis in a subset of patients [3]. Despite the relatively benign course in most carriers, EBV reactivation is considered as a risk-factor both for malignant transformation and autoimmune diseases. The ability of the EBV encoded protein 1566LMP-1 to induce T-cell-independent immunoglobulin class switch DNA recombination and BAFF, a B-cell activating factor, that rescues self-reactive T cells, is considered to play an important role in the pathogenesis of EBV-related autoimmune and lymphoproliferative disease [4]. EBV is causatively linked to nasopharyngeal carcinoma and B-cell malignant diseases such as endemic Burkitt's lymphoma, Hodgkin's lymphoma and posttransplant lymphoproliferative diseases (PTLD) [5][6][7]. Recent data suggest that EBV is associated with various autoimmune diseases as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis and primary Sjögren's syndrome [8,9]. Chronic active EBV infection can also cause Chronic Fatigue Syndrome, which is frequently associated with autoimmune thyreoiditis [10].The EBV cycle has two distinct stages, the latent infection where the genome is maintained at a constant copy number per cell and limited regions of the genome are expressed and the lytic cycle w...

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Intrathymic epstein‐barr virus infection is not a prominent feature of myasthenia gravis

Kakalacheva

Maurer

Tackenberg

et al. 2011

Annals of Neurology

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Lymph node-type T- and B-cell infiltrates with germinal centers are characteristic features of the hyperplastic thymus in early onset myasthenia gravis (EOMG).Epstein-Barr virus (EBV) infection confers survival advantages on B cells, and has recently been implicated in tertiary lymphoid tissue formation in EOMG. We evaluated the frequency of intrathymic EBV-infected B-lineage cells and antiviral immune responses in treatment-naive patients with EOMG. Real-time polymerase chain reaction was performed to quantify the content of genomic EBV DNA (BamHI-W repeat region) in thymic cell suspensions. Serial paraffin sections of EOMG thymi were analyzed for the presence of EBV-encoded RNA by in situ hybridization and for viral gene expression by immunohistochemistry. Humoral and cellular immune responses to viral antigens were quantified by enzyme-linked immunosorbent assay and flow cytometry-based intracellular cytokine staining. We detected minimal levels of viral DNA-corresponding to single viral genomes-in only 6 of 16 hyperplastic EOMG thymi, indicating extreme rarity of viral copy numbers in the investigated thymic samples. That was confirmed by similar rarity of EBV-encoded RNA and viral proteins identified in thymic sections. Furthermore, EBV-specific T- and B-cell responses were unchanged in patients with EOMG. These findings do not support an etiologic role for EBV in the initiation of EOMG.

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Priming of protective T cell responses against virus-induced tumors in mice with human immune system components

Cited by 272 publications

References 47 publications

Animal models of Epstein Barr virus infection

Animal models of Epstein Barr virus infection

Human peripheral blood and bone marrow Epstein–Barr virus‐specific T‐cell repertoire in latent infection reveals distinct memory T‐cell subsets

Intrathymic epstein‐barr virus infection is not a prominent feature of myasthenia gravis

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