Quantitative analysis of EBV-specific CD4/CD8 T cell numbers, absolute CD4/CD8 T cell numbers and EBV load in solid organ transplant recipients with PLTD

Sebelin-Wulf, Kathrin; Nguyen, Tan Van; Oertel, Stephan; Papp-Váry, Matthias; Trappe, Ralf Ulrich; Schulzki, Antje; Pezzutto, Antonio; Riess, Hanno; Subklewe, Marion

doi:10.1016/j.trim.2006.10.006

Cited by 85 publications

(53 citation statements)

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“…3C). A recent study suggests low numbers of CD4 1 cells as a risk factor for the development of PTLD in solid organ transplant recipients [60]. Patients receiving T-cell therapy for EBV-positive PTLD have better responses when the infused CTL lines have higher numbers of CD4 1 T cells [61].…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…The recent identification of low levels of endogenous CD4 ϩ T cells as an important risk factor for the development of EBV-associated diseases in immunosuppressed patients (35) and of better clinical responses in patients with PTLD receiving EBV-specific T-cell lines that contained higher proportions of CD4 ϩ T cells (14) imply an important role for CD4 ϩ T cells in the control of EBV infection in vivo. EBV-specific CD4 ϩ T cells in LCL-stimulated T-cell preparations are almost exclusively directed against structural antigens of the virus (1), which are efficiently presented on MHC-II following the receptor-mediated uptake of released viral particles (2).…”

Section: Discussionmentioning

confidence: 99%

“…First, low numbers of endogenous CD4 ϩ T cells has been identified as an important risk factor for the development of EBV-associated diseases in immunosuppressed patients (35). Second, patients with PTLD showed better clinical responses in a recent phase II trial when the infused T-cell lines contained higher proportions of CD4 ϩ T cells (14).…”

Section: Cd4mentioning

confidence: 99%

Standardized and Highly Efficient Expansion of Epstein-Barr Virus-Specific CD4 ⁺ T Cells by Using Virus-Like Particles

Adhikary

Behrends

Feederle

et al. 2008

J Virol

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“…EBV control is rather mediated by cytotoxic T lymphocytes (37): accordingly, in our patient series, lymphocyte counts inversely correlated to EBV-DNA. In this line, Sebelin-Wulf and colleagues observed an inverse correlation between EBV copies and lymphocyte counts, in particular CD4þ cells, in patients with EBV-associated posttransplant lymphomas (38). It will be interesting to explore whether this association reflects a specific defect in the circulating T cell populations, unable to control EBV expansion.…”

Section: Cd68mentioning

confidence: 95%

The Viral Load of Epstein–Barr Virus (EBV) DNA in Peripheral Blood Predicts for Biological and Clinical Characteristics in Hodgkin Lymphoma

Hohaus

Santangelo

Giachelia

et al. 2011

Clinical Cancer Research

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Purpose: The Epstein-Barr virus (EBV) is present in the malignant Hodgkin/Reed-Sternberg (HRS) cells of 20% to 40% cases of Hodgkin lymphoma (HL) in Western countries. We were interested in the detection and quantification of cell-free plasma EBV-DNA as an indicator of biological and clinical characteristics in EBV-associated HL.Experimental Design: EBV was detected in peripheral blood compartments (whole blood, plasma, and mononuclear cells) at diagnosis by real-time PCR for the EBNA (EB nuclear antigen) region (n ¼ 93) and in HRS cells by in situ hybridization for EBV-encoded small RNAs (EBER; n ¼ 63). These data were correlated to histological and clinical characteristics, EBV serology, circulating cell-free DNA, and interleukin (IL)-6 levels.Results: Detection of EBV-DNA in plasma had a high specificity (90%), but a relatively low sensitivity (65%) to predict for EBV association. The viral load was higher in patients with advanced stage disease, older age in the presence of B-symptoms, and international prognostic score more than 2. The presence of EBV in HRS cells and higher plasma EBV-DNA copy numbers correlated to an increased frequency of tumor-infiltrating CD68þ macrophages in lymph node biopsies. Plasma EBV-DNA load correlated to circulating cell-free DNA and IL-6 levels, and inversely correlated to lymphocyte counts and EBNA1 antibody titers.Conclusion: Although the presence of EBV-DNA in peripheral blood cannot be regarded as a surrogate marker for EBER, the plasma EBV-DNA load at HL diagnosis is an indicator of disease activity and biological characteristics associated with negative prognosis. Moreover, the inverse correlation to EBNA1 antibody titers and lymphocyte counts may indicate a reduction in immunosurveillance, favoring the expansion of EBV-HRS cells in HL. Clin Cancer Res; 17(9); 2885-92. Ó2011 AACR.

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Quantitative analysis of EBV-specific CD4/CD8 T cell numbers, absolute CD4/CD8 T cell numbers and EBV load in solid organ transplant recipients with PLTD

Cited by 85 publications

References 44 publications

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

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

Standardized and Highly Efficient Expansion of Epstein-Barr Virus-Specific CD4 ⁺ T Cells by Using Virus-Like Particles

The Viral Load of Epstein–Barr Virus (EBV) DNA in Peripheral Blood Predicts for Biological and Clinical Characteristics in Hodgkin Lymphoma

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Quantitative analysis of EBV-specific CD4/CD8 T cell numbers, absolute CD4/CD8 T cell numbers and EBV load in solid organ transplant recipients with PLTD

Cited by 85 publications

References 44 publications

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

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

Standardized and Highly Efficient Expansion of Epstein-Barr Virus-Specific CD4 + T Cells by Using Virus-Like Particles

The Viral Load of Epstein–Barr Virus (EBV) DNA in Peripheral Blood Predicts for Biological and Clinical Characteristics in Hodgkin Lymphoma

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Standardized and Highly Efficient Expansion of Epstein-Barr Virus-Specific CD4 ⁺ T Cells by Using Virus-Like Particles