Ratio between Epstein-Barr viral load and anti-Epstein-Barr virus specific T-cell response as a predictive marker of posttransplant lymphoproliferative disease1

Smets, Françoise; Latinne, Dominique; Bazin, Hervé; Reding, Raymond; Otte, Jean-Bernard; Buts, Jean-Paul; Sokal, Étienne

doi:10.1097/00007890-200205270-00014

Cited by 185 publications

(125 citation statements)

References 22 publications

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“…EBV viral loads correlated positively with the frequency of EBV-specific CD69 ϩ CD8 ϩ T cells producing IFN-␥ (with a similar trend in CD8 ϩ T cells producing TNF-␣) and with the frequency of BMLF1 lytic peptide-specific CD8 ϩ T cells, as measured by HLA-A2 tetramers. A positive correlation between EBV viral loads and EBV-specific CD8 ϩ T cell responses is consistent with findings from studies of patients with HIV infection and organ transplantation (31,40,41). In HIV-infected patients with long term nonprogression, EBV viral loads in PBMCs were positively associated with the number of functional EBV-specific CD8 ϩ T cells measured by ELISPOT (41).…”

Section: The Increased Frequency Of Ebv-specific Cd4supporting

confidence: 86%

“…As inferred above, EBV-related lymphoproliferative disease has been observed after organ transplantations and in association with AIDS (13,14), and the infusion of EBV-specific CD4 ϩ and CD8 ϩ T cells prevent and lead to resolution of EBV-associated lymphoma in patients following bone marrow transplantation (22). The development of EBV-associated lymphoproliferative disease closely correlates with the decline of EBV-specific T cell responses and the rise of EBV viral loads (40). Notably, however, EBV viral loads in our patients with SLE, at ϳ200 DNA copies/10 5 PBMCs, were not as high as those in patients with EBV-associated lymphoproliferative disease, where they may reach 10,000 DNA copies/10 5 PBMCs (40, 41) (J. G. Howe, unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Defective Control of Latent Epstein-Barr Virus Infection in Systemic Lupus Erythematosus

Kang

Quan

Nolasco

et al. 2004

The Journal of Immunology

224

187

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EBV infection is more common in patients with systemic lupus erythematosus (SLE) than in control subjects, suggesting that this virus plays an etiologic role in disease and/or that patients with lupus have impaired EBV-specific immune responses. In the current report we assessed immune responsiveness to EBV in patients with SLE and healthy controls, determining virus-specific T cell responses and EBV viral loads using whole blood recall assays, HLA-A2 tetramers, and real-time quantitative PCR. Patients with SLE had an ∼40-fold increase in EBV viral loads compared with controls, a finding not explained by disease activity or immunosuppressive medications. The frequency of EBV-specific CD69+ CD4+ T cells producing IFN-γ was higher in patients with SLE than in controls. By contrast, the frequency of EBV-specific CD69+ CD8+ T cells producing IFN-γ in patients with SLE appeared lower than that in healthy controls, although this difference was not statistically significant. These findings suggest a role for CD4+ T cells in controlling, and a possible defect in CD8+ T cells in regulating, increased viral loads in lupus. These ideas were supported by correlations between viral loads and EBV-specific T cell responses in lupus patients. EBV viral loads were inversely correlated with the frequency of EBV-specific CD69+ CD4+ T cells producing IFN-γ and were positively correlated with the frequencies of CD69+ CD8+ T cells producing IFN-γ and with EBV-specific, HLA-A2 tetramer-positive CD8+ T cells. These results demonstrate that patients with SLE have defective control of latent EBV infection that probably stems from altered T cell responses against EBV.

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Section: The Increased Frequency Of Ebv-specific Cd4supporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Defective Control of Latent Epstein-Barr Virus Infection in Systemic Lupus Erythematosus

Kang

Quan

Nolasco

et al. 2004

The Journal of Immunology

224

187

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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. EBV nuclear antigen 1 (EBNA-1) is a latent antigen that is invariably expressed in all EBV-infected proliferating cells [16] and associated malignancies [17], being crucial for viral persistence by acting as replication and transcription factor [18], without viral particle formation.…”

mentioning

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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“…Ancak bu analizler çok pahalıdır ve rutin laboratuvarlarda uygulanmamaktadır. 84,85 ■ Radyolojik değerlendirme: PTLH düşünü-len hastada baştan pelvise "head to pelvis" radyolojik değerlendirme önerilmektedir. İlk tanıda olası SSS lezyonunu atlamamak adına kraniyal bilgisayarlı tomografi (BT) veya manyetik rezonans görüntüleme (MRG) önerilmekte; pulmoner lezyon için yüksek çözünürlüklü BT (HRCT) ve lezyon saptanırsa biyopsi önerilmekte; abdominal lezyonlar için ultrasonografi (USG), BT veya MRG önerilmekte; intestinal hemoraji, persistan diyare, açıklanamayan kilo kaybı varlığında gastrointestinal sistem (GİS) endoskopisi, kullanımı standart olmasa da florodeoksiglukoz pozitron emisyon tomografi (FDG-PET) önerilmektedir.…”

Section: 79unclassified

Posttransplant Lymphoproliferative Diseases During Childhood: Review

Ince¹,

Demirağ²,

Vergin³

et al. 2015

Turkiye Klinikleri J Pediatr

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Ö ÖZ ZE ET T Posttransplant lenfoproliferatif hastalıklar (PTLH), solid organ transplantasyonu veya allojeneik hematopoietik kök hücre transplantasyonu (HKHT) sonrası immünsupresyona ikincil gelişen, benign poliklonal lenfoid proliferasyon ile malign monoklonal lenfoid proliferasyon arası spektruma sahip bir hastalık grubudur. Klinik tabloda belirgin morbidite ve mortalite riski mevcuttur, insidansı %1-30 arasında bildirilmektedir. Hastanın transplantasyon yaşı ve transplantasyon öncesinde Epstein-Barr virus (EBV) ile enfekte olma durumu, transplante edilen organın tipi, kullanılan immünsupresif rejim PTLH gelişmesini etkilemektedir. Dünya Sağ-lık Örgütü, PTLH için dört farklı morfolojik lezyon tanımlamıştır: Erken PTLH, polimorfik PTLH, monomorfik PTLH ve klasik Hodgkin lenfoma benzeri lezyonlar. Hasta değerlendirilirken alıcı ve vericinin EBV/sitomegalovirüs serolojisi; allogreftin tipi; transplantasyon sonrası ne kadar zaman geçtiği; alıcının transplantta yaşı dikkate alınmalıdır. PTLH immünolojik ve onkolojik bir hastalıktır. Günümüzde çocukluk çağı PTLH tedavisinde preemptif yaklaşımda uygulanan immünsupresyonun azaltılması, antiviral ajanların (± immünglobulin) yanı sıra standart tedavi yaklaşımı antrasiklin içermeyen, siklofosfamid, prednizolon ve rituksimab içeren azaltılmış doz kemoterapi uygulanmasıdır. Hedefe yönelik immün temele dayalı kombine tedavilerin kullanımı, rituksimab ve üçüncü parti EBV spesifik T-lenfositlerin kullanılmasıyla PTLH tedavisi güncel araştırma konularıdır. Günümüzde Türkiye'de giderek artan sayıda pediatrik solid organ transplantasyonu ve hematopoietik kök hücre transplantasyonu yapılmakta ve beraberinde giderek artan sayıda PTLH gelişen çocuk olgular bildirilmektedir. Ülkemizde çocuk hastalara özel bir transplantasyon kayıt sisteminin ve transplantasyon yapılan çocuk hasta grubunun gerek PTLH gelişme riski gerekse diğer onkolojik hastalıkların gelişme riski açısından standart bir izlem politikasının geliştirilmesine ihtiyaç bulunmaktadır. A An na ah h t ta ar r K Ke e l li i m me e l le er r: : Lenfoproliferatif bozukluklar; kemik iliği transplantasyonu; organ transplantasyonu; rituksimab; antineoplastik birleşik kemoterapi protokolleri A AB BS S T TR RA AC CT T Posttransplant lymphoproliferative diseases (PTLDs) which develop after solid organ transplantation and hematopoietic stem cell transplantation due to immune supression have a spectrum ranging from benign polyclonal lymphoid proliferation to malign monoclonal lymphoid proliferation. Its mortality and morbidity risks are significant with a reported incidence rate between 1-30%. The patient's age at transplantation, pretransplant Epstein-Barr virus (EBV) infection, the type of organ transplant, and used immunosuppressive regime have effects on PTLD development. The World Health Organization defines four different morphologic lesions for PTLD: Early PTLD, polymorphic PTLD, monomorphic PTLD, and classic Hodgkin lymphoma-like PTLD. While evaluating a patient, donor and recipient EBV/cytomegalovirus serologies; allograft ty...

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Ratio between Epstein-Barr viral load and anti-Epstein-Barr virus specific T-cell response as a predictive marker of posttransplant lymphoproliferative disease1

Abstract: We conclude that high viral load is systematic in patients who underwent primary EBV infection and is indicative of the PTLD risk only if there is low concomitant cellular immune response. Healing from PTLD requires modulation of immunosuppression, and appearance of EBV-TL.

Cited by 185 publications

References 22 publications

Defective Control of Latent Epstein-Barr Virus Infection in Systemic Lupus Erythematosus

Defective Control of Latent Epstein-Barr Virus Infection in Systemic Lupus Erythematosus

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

Posttransplant Lymphoproliferative Diseases During Childhood: Review

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