Management of Epstein–Barr virus-related post-transplant lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation

Liu, Li; Liu, Qifa; Feng, Sizhou

doi:10.1177/2040620720910964

Cited by 20 publications

(11 citation statements)

References 69 publications

(206 reference statements)

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“…Most patients had a history of organ transplantation, immunosuppression, and immune deficiency, and EBER positivity was detected in tumor cells. Studies have shown that transplantation, immunosuppression, and immune deficiency can induce primary infection or reactivation of EBV ( 19 , 20 ). However, among the 382 cases of FL reported by Mackrides et al.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathologic study of mantle cell lymphoma with epstein-barr virus infection: A case series and literature review

Zhou

et al. 2022

Front. Oncol.

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BackgroundMantle cell lymphoma (MCL) with Epstein–Barr virus (EBV) infection is rarely reported. The objective of this study was to analyze the prevalence and clinicopathological features of MCL with EBV infection in the largest series thus far.MethodsAfter screening 138 cases of MCL, we identified eight cases of MCL with EBV infection.ResultsMost of them (7/8) had non-neoplastic bystander cells with positivity for EBV and no expression of latent membrane protein 1 (LMP1) and EBV nuclear antigen 2 (EBNA2). The cases of MCL with EBER positivity did not have abnormal immune function or other lymphomas. Moreover, their histopathological morphology was indicative of classical MCL. Cases of MCL with EBER positivity exhibited statistically significant differences in lactate dehydrogenase, anemia status, and MCL international prognostic index grouping (P=0.008, P=0.02, P=0.001, and P=0.011, respectively). The differences between the two groups in age, sex ratio, clinical manifestations, and immunohistochemical phenotypes were not statistically significant.ConclusionsThe incidence of MCL with EBV infection was low (5.8%). Clinicopathologically, cases of MCL with EBER positivity were similar to their EBV-negative counterparts. Our findings revealed that most cells infected by EBV in MCL are background cells rather than tumor cells. This is inconsistent with data from previous studies, indicating that tumor cells in MCL may not be prone to EBV infection.

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Section: Discussionmentioning

confidence: 99%

Clinicopathologic study of mantle cell lymphoma with epstein-barr virus infection: A case series and literature review

Zhou

et al. 2022

Front. Oncol.

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“…In experimental models, delta-2+ lymphocytes proved to be cytotoxic against EBV infected cells ( 98 ); in another study, delta-2+ recovery seemed to exert a protective role from EBV reactivation ( 99 ). The same authors showed that mycophenolate-driven inhibition of delta-2+ gamma-delta lymphocytes could play a role in the pathogenesis of PTLD, at least in the haploidentical setting ( 100 ).…”

Section: Management Of Viral Infections After Hsctmentioning

confidence: 99%

Viral Infections in HSCT: Detection, Monitoring, Clinical Management, and Immunologic Implications

et al. 2021

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In spite of an increasing array of investigations, the relationships between viral infections and allogeneic hematopoietic stem cell transplantation (HSCT) are still controversial, and almost exclusively regard DNA viruses. Viral infections per se account for a considerable risk of morbidity and mortality among HSCT recipients, and available antiviral agents have proven to be of limited effectiveness. Therefore, an optimal management of viral infection represents a key point in HSCT strategies. On the other hand, viruses bear the potential of shaping immunologic recovery after HSCT, possibly interfering with control of the underlying disease and graft-versus-host disease (GvHD), and eventually with HSCT outcome. Moreover, preliminary data are available about the possible role of some virome components as markers of immunologic recovery after HSCT. Lastly, HSCT may exert an immunotherapeutic effect against some viral infections, notably HIV and HTLV-1, and has been considered as an eradicating approach in these indications.

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“…Reduction of immunosuppression (RI) as tolerated is a cornerstone to restore EBV-directed immunity; however, it must be balanced against the risk of graft-versus-hostdisease (GvHD) or organ graft rejection (5,11). Treatment with rituximab, a chimeric monoclonal antibody (mAb), with or without chemotherapy is currently accepted as the first-line choice for preemptive intervention and targeted treatment (12) in a broad variety of CD20 + B-cell malignancies, including EBV-positive lymphomas. For EBV-associated PTLD, rituximab treatment resulted in complete remission in more than 60% of patients (12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Reinforcement of cell-mediated immunity driven by tumor-associated Epstein-Barr virus (EBV)-specific T cells during targeted B-cell therapy with rituximab

et al. 2023

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IntroductionIn immunocompromised patients, Epstein-Barr virus (EBV) infection or reactivation is associated with increased morbidity and mortality, including the development of B-cell lymphomas. The first-line treatment consists of reduction of immunosuppression and administration of rituximab (anti-CD20 antibody). Furthermore, the presence of EBV-specific T cells against latent EBV proteins is crucial for the control of EBV-associated diseases. Therefore, in addition to effective treatment strategies, appropriate monitoring of T cells of high-risk patients is of great importance for improving clinical outcome. In this study, we hypothesized that rituximab-mediated lysis of malignant EBV-infected B cells leads to the release and presentation of EBV-associated antigens and results in an augmentation of EBV-specific effector memory T-cell responses.MethodsEBV-infected B lymphoblastoid cell lines (B-LCLs) were used as a model for EBV-associated lymphomas, which are capable of expressing latency stage II and III EBV proteins present in all known EBV-positive malignant cells. Rituximab was administered to obtain cell lysates containing EBV antigens (ACEBV). Efficiency of cross-presentation of EBV-antigen by B-LCLs compared to cross-presentation by professional antigen presenting cells (APCs) such as dendritic cells (DCs) and B cells was investigated by in vitro T-cell immunoassays. Deep T-cell profiling of the tumor-reactive EBV-specific T cells in terms of activation, exhaustion, target cell killing, and cytokine profile was performed, assessing the expression of T-cell differentiation and activation markers as well as regulatory and cytotoxic molecules by interferon-γ (IFN-γ) EliSpot assay, multicolor flow cytometry, and multiplex analyses.ResultsBy inhibiting parts of the cross-presentation pathway, B-LCLs were shown to cross-present obtained exogenous ACEBV-derived antigens mainly through major histocompatibility complex (MHC) class I molecules. This mechanism is comparable to that for DCs and B cells and resulted in a strong EBV-specific CD8+ cytotoxic T-cell response. Stimulation with ACEBV-loaded APCs also led to the activation of CD4+ T helper cells, suggesting that longer peptide fragments are processed via the classical MHC class II pathway. In addition, B-LCLs were also found to be able to take up exogenous antigens from surrounding cells by endocytosis leading to induction of EBV-specific T-cell responses although to a much lesser extent than cross-presentation of ACEBV-derived antigens. Increased expression of activation markers CD25, CD71 and CD137 were detected on EBV-specific T cells stimulated with ACEBV-loaded APCs, which showed high proliferative and cytotoxic capacity as indicated by enhanced EBV-specific frequencies and increased secretion levels of cytotoxic effector molecules (e.g. IFN-γ, granzyme B, perforin, and granulysin). Expression of the regulatory proteins PD-1 and Tim-3 was induced but had no negative impact on effector T-cell functions.ConclusionIn this study, we showed for the first time that rituximab-mediated lysis of EBV-infected tumor cells can efficiently boost EBV-specific endogenous effector memory T-cell responses through cross-presentation of EBV-derived antigens. This promotes the restoration of antiviral cellular immunity and presents an efficient mechanism to improve the treatment of CD20+ EBV-associated malignancies. This effect is also conceivable for other therapeutic antibodies or even for therapeutically applied unmodified or genetically modified T cells, which lead to the release of tumor antigens after specific cell lysis.

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Management of Epstein–Barr virus-related post-transplant lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation

Cited by 20 publications

References 69 publications

Clinicopathologic study of mantle cell lymphoma with epstein-barr virus infection: A case series and literature review

Clinicopathologic study of mantle cell lymphoma with epstein-barr virus infection: A case series and literature review

Viral Infections in HSCT: Detection, Monitoring, Clinical Management, and Immunologic Implications

Reinforcement of cell-mediated immunity driven by tumor-associated Epstein-Barr virus (EBV)-specific T cells during targeted B-cell therapy with rituximab

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