Effective and long-term control of EBV PTLD after transfer of peptide-selected T cells

Moosmann, Andreas; Bigalke, Iris; Tischer, Johanna; Schirrmann, Leah; Kasten, Julitta; Tippmer, Stefanie; Leeping, Marina; Prevalsek, Dusan; Jaeger, Gundula; Ledderose, Georg; Mautner, Josef; Hammerschmidt, Wolfgang; Schendel, Dolores J.; Kolb, Hans‐Jochem

doi:10.1182/blood-2009-08-236356

Cited by 199 publications

(172 citation statements)

References 59 publications

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“…Conversely, the absence of EBV-specific CD8 + T cells predicts the emergence of EBVassociated disease in patients after stem cell transplantation or when afflicted with AIDS (1-3). Dangerous EBV-mediated complications can be reversed or prevented by transfer of EBVspecific T cells (4,5), which further confirms the important role of continuous T-cell control of EBV infection. Among EBVspecific T cells, CD8 + T cells predominate; about 0.05-1% of all CD8 + T cells in healthy donors are typically specific for EBV latent antigens and about twice as many for lytic antigens (6,7).…”

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confidence: 52%

“…For immunosuppressed patients, it appears clear that T-cell deficiency favors appearance of latency III malignancies (3), that adoptive T-cell therapy can prevent this (4,5), and that T-cell therapy fails if the EBV strain in question does not express crucial CD8 + T-cell epitopes in a latency III protein (50). Regarding infection in immunocompetent carriers, there were early arguments against a T-cell surveillance of latency III (51), but later studies showed that latency III-associated CD8 + T-cell epitopes are in fact under a selective pressure that depends on the frequency of HLA class I allotypes in a population (52,53).…”

Section: Discussionmentioning

confidence: 99%

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Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 ⁺ T cells

Albanese

Tagawa

Bouvet

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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133

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Infection with Epstein-Barr virus (EBV) affects most humans worldwide and persists life-long in the presence of robust virus-specific T-cell responses. In both immunocompromised and some immunocompetent people, EBV causes several cancers and lymphoproliferative diseases. EBV transforms B cells in vitro and encodes at least 44 microRNAs (miRNAs), most of which are expressed in EBV-transformed B cells, but their functions are largely unknown. Recently, we showed that EBV miRNAs inhibit CD4 + T-cell responses to infected B cells by targeting IL-12, MHC class II, and lysosomal proteases. Here we investigated whether EBV miRNAs also counteract surveillance by CD8 + T cells. We have found that EBV miRNAs strongly inhibit recognition and killing of infected B cells by EBV-specific CD8 + T cells through multiple mechanisms. EBV miRNAs directly target the peptide transporter subunit TAP2 and reduce levels of the TAP1 subunit, MHC class I molecules, and EBNA1, a protein expressed in most forms of EBV latency and a target of EBV-specific CD8 + T cells. Moreover, miRNAmediated down-regulation of the cytokine IL-12 decreases the recognition of infected cells by EBV-specific CD8 + T cells. Thus, EBV miRNAs use multiple, distinct pathways, allowing the virus to evade surveillance not only by CD4 + but also by antiviral CD8 + T cells.adaptive immunity | immune evasion | herpesvirus | CD8 T cells | microRNA E pstein-Barr virus (EBV) is a ubiquitous herpesvirus that infects the majority of the human population worldwide. Although EBV infection persists for life, most carriers remain asymptomatic due to a stringent control by virus-specific immunity. An important component of this immunity is EBV-specific CD8 + T cells, which often expand to high numbers in healthy carriers or after primary infection. Conversely, the absence of EBV-specific CD8 + T cells predicts the emergence of EBVassociated disease in patients after stem cell transplantation or when afflicted with AIDS (1-3). Dangerous EBV-mediated complications can be reversed or prevented by transfer of EBVspecific T cells (4, 5), which further confirms the important role of continuous T-cell control of EBV infection. Among EBVspecific T cells, CD8 + T cells predominate; about 0.05-1% of all CD8 + T cells in healthy donors are typically specific for EBV latent antigens and about twice as many for lytic antigens (6, 7).EBV predominantly infects B cells and establishes a latent infection before production of progeny virus becomes possible (8). Four distinct programs of EBV latent infection have been defined according to their expression profiles of latent viral genes (9-11). One of these programs, known as latency III or the "growth program," is characterized by the expression of a restricted set of approximately eight viral proteins, which activate B cells and drive their proliferation, thus increasing the viral reservoir. Latency III is found in EBV-associated malignancies in immunosuppressed patients (9) and likely reemerges continuously in healthy carriers (9, 12), indicati...

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confidence: 52%

Section: Discussionmentioning

confidence: 99%

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 ⁺ T cells

Albanese

Tagawa

Bouvet

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

132

133

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“…88,89 Rapid isolation strategies such as 'gamma catch' can be utilized when VSTs occur at high frequency in the donor's blood. This strategy has been successfully used in patients with CMV disease or viremia, with a response rate of 83%, 90 EBV, with a response rate of 50-70% 91,92 and ADV, with responses in 5 of 6 patients in a small study. 93 Adoptive transfer of VSTs from an adult stem cell donor is effective as prophylaxis and treatment for treatment-refractory EBV, CMV and ADV infections.…”

Section: Infectionmentioning

confidence: 99%

Umbilical cord blood graft engineering: challenges and opportunities

Thompson

Rezvani

Hosing

et al. 2015

Bone Marrow Transplant

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We are entering a very exciting era in umbilical cord blood transplantation (UCBT), where many of the associated formidable challenges may become treatable by ex vivo graft manipulation and/or adoptive immunotherapy utilizing specific cellular products. We envisage the use of double UCBT rather than single UCBT for most patients; this allows for greater ability to treat larger patients as well as to manipulate the graft. Ex vivo expansion and/or fucosylation of one cord will achieve more rapid engraftment, minimize the period of neutropenia and also give certainty that the other cord will provide long-term engraftment/immune reconstitution. The non-expanded (and future dominant) cord could be chosen for characteristics such as better HLA matching to minimize GvHD, or larger cell counts to enable part of the unit to be utilized for the development of specific cellular therapies such as the production of virus-specificT-cells or chimeric-antigen receptor T-cells which are reviewed in this study.

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“…These CTLs were also effective in three of six patients with manifest EBV-PTLD. 39 Cellular therapies after haploidentical HCT or in cord blood recipients EBV-PTLD after haploidentical HCT was successfully treated using blood cells from the haploidentical donor as CTL source, expanded rapidly by a similar protocol. A CR was achieved in one exemplary case.…”

Section: Clinical and Laboratory Presentationmentioning

confidence: 99%

EBV-induced post transplant lymphoproliferative disorders: a persisting challenge in allogeneic hematopoetic SCT

Rasche

Kapp

Einsele

et al. 2013

Bone Marrow Transplant

115

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EBV-induced post transplantation lymphoproliferative disorder (EBV-PTLD) is a life-threatening complication after allogeneic hematopoietic cell transplantation. Profound T-cell depletion of the allograft represents a major risk factor for EBV-PTLD. With regard to the increasing use of alternative stem cell sources such as cord blood or purified haploidentical stem cell grafts both associated with impaired immune reconstitution, the frequent occurrence of EBV-PTLD demands particular vigilance on laboratory changes and early symptoms. Here we have summarized today's knowledge about EBV-PTLD in a comprehensive review explaining the underlying mechanisms of EBV-based transformation, EBV-PTLD development, clinical presentation, incidence, diagnosis, screening, therapy and prognosis. In this context, we emphasize on the necessity of regularly applied screening tools and pre-emptive treatment strategies including anti-CD20 Abs particularly in high-risk patients to avoid disease progression to malignant lymphoma. Although EBV-PTLD has always been associated with a high mortality rate, novel immunotherapeutic approaches such as the transfer of EBV-specific T cells nowadays offer improved chances of disease control even at late stages.

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Effective and long-term control of EBV PTLD after transfer of peptide-selected T cells

Abstract: Posttransplantation lymphoproliferative disease (PTLD) associated with EpsteinBarr virus (EBV) is

Cited by 199 publications

References 59 publications

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 ⁺ T cells

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 ⁺ T cells

Umbilical cord blood graft engineering: challenges and opportunities

EBV-induced post transplant lymphoproliferative disorders: a persisting challenge in allogeneic hematopoetic SCT

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Effective and long-term control of EBV PTLD after transfer of peptide-selected T cells

Abstract: Posttransplantation lymphoproliferative disease (PTLD) associated with EpsteinBarr virus (EBV) is

Cited by 199 publications

References 59 publications

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 + T cells

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 + T cells

Umbilical cord blood graft engineering: challenges and opportunities

EBV-induced post transplant lymphoproliferative disorders: a persisting challenge in allogeneic hematopoetic SCT

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Product

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Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 ⁺ T cells

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 ⁺ T cells