Rapid reconstitution of Epstein-Barr virus–specific T lymphocytes following allogeneic stem cell transplantation

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2814-2821 ◽  
Author(s):  
Natalie A. Marshall ◽  
John Greg Howe ◽  
Richard Formica ◽  
Diane Krause ◽  
John E. Wagner ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cd8 T Cells ◽  
Epstein Barr Virus ◽  
Hla Class I ◽  
Barr Virus ◽  
Matched Sibling ◽  
Epstein Barr

Epstein-Barr virus (EBV)–specific CD8 T lymphocytes are present at remarkably high frequencies in healthy EBV+individuals and provide protection from EBV-associated lymphoproliferative diseases. Allogeneic peripheral blood stem cell transplantation (allo-PBSCT) is a commonly used therapy in which T-cell surveillance for EBV is temporarily disrupted. Herein, human leukocyte antigen (HLA) class I tetramers were used to investigate the reestablishment of the EBV-specific CD8 T-cell repertoire in patients following allo-PBSCT. CD8+ T cells specific for lytic and latent cycle–derived EBV peptides rapidly repopulate the periphery of matched sibling allo-PBSCT patients. The relative frequencies of T cells specific for different EBV peptides in transplantation recipients closely reflect those of their respective donors. Investigation of patients at monthly intervals following unmanipulated allo-PBSCT demonstrated that the frequency of EBV-specific T cells correlates with the number of EBV genome copies in the peripheral blood and that expansion of EBV-specific T-cell populations occurs even in the setting of immunosuppressive therapy. In contrast, patients undergoing T-cell–depleted or unrelated cord blood transplantation have undetectable EBV-specific T cells, even in the presence of Epstein-Barr viremia. The protective shield provided by EBV-specific CD8 T cells is rapidly established following unmanipulated matched sibling allo-PBSCT and demonstrates that HLA class I tetramers complexed with viral peptides can provide direct and rapid assessment of pathogen-specific immunity in this and other vulnerable patient populations.

Rapid reconstitution of Epstein-Barr virus–specific T lymphocytes following allogeneic stem cell transplantation

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2814-2821 ◽  
Author(s):  
Natalie A. Marshall ◽  
John Greg Howe ◽  
Richard Formica ◽  
Diane Krause ◽  
John E. Wagner ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cd8 T Cells ◽  
Epstein Barr Virus ◽  
Hla Class I ◽  
Barr Virus ◽  
Matched Sibling ◽  
Epstein Barr

Abstract Epstein-Barr virus (EBV)–specific CD8 T lymphocytes are present at remarkably high frequencies in healthy EBV+individuals and provide protection from EBV-associated lymphoproliferative diseases. Allogeneic peripheral blood stem cell transplantation (allo-PBSCT) is a commonly used therapy in which T-cell surveillance for EBV is temporarily disrupted. Herein, human leukocyte antigen (HLA) class I tetramers were used to investigate the reestablishment of the EBV-specific CD8 T-cell repertoire in patients following allo-PBSCT. CD8+ T cells specific for lytic and latent cycle–derived EBV peptides rapidly repopulate the periphery of matched sibling allo-PBSCT patients. The relative frequencies of T cells specific for different EBV peptides in transplantation recipients closely reflect those of their respective donors. Investigation of patients at monthly intervals following unmanipulated allo-PBSCT demonstrated that the frequency of EBV-specific T cells correlates with the number of EBV genome copies in the peripheral blood and that expansion of EBV-specific T-cell populations occurs even in the setting of immunosuppressive therapy. In contrast, patients undergoing T-cell–depleted or unrelated cord blood transplantation have undetectable EBV-specific T cells, even in the presence of Epstein-Barr viremia. The protective shield provided by EBV-specific CD8 T cells is rapidly established following unmanipulated matched sibling allo-PBSCT and demonstrates that HLA class I tetramers complexed with viral peptides can provide direct and rapid assessment of pathogen-specific immunity in this and other vulnerable patient populations.

Adoptive Transfer of Epstein-Barr Virus (EBV) Nuclear Antigen 1–Specific T Cells As Treatment for EBV Reactivation and Lymphoproliferative Disorders After Allogeneic Stem-Cell Transplantation

2013 ◽  
Vol 31 (1) ◽  
pp. 39-48 ◽  
Author(s):  
Vanya Icheva ◽  
Simone Kayser ◽  
Daniel Wolff ◽  
Sebastian Tuve ◽  
Christina Kyzirakos ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Adoptive Transfer ◽  
Epstein Barr Virus ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Epstein Barr

Purpose Reactivation of Epstein-Barr virus (EBV) after allogeneic stem-cell transplantation (SCT) can lead to severe life-threatening infections and trigger post-transplantation lymphoproliferative disease (PTLD). Since EBV-specific T cells could prevent PTLD, cellular immunotherapy has been a promising treatment option. However, generation of antigen-specific T-cell populations has been difficult within a short time frame. Patients and Methods To improve availability in urgent clinical conditions, we developed a rapid protocol for isolation of polyclonal EBV nuclear antigen 1 (EBNA-1) –specific T cells by using an interferon gamma (IFN-γ) capture technique. Results We report on the use of adoptive transfer of EBNA-1–specific T cells in 10 pediatric and adult patients with EBV viremia and/or PTLD after SCT. No acute toxicity or graft-versus-host disease (GVHD) of more than grade 2 occurred as a result of adoptive T-cell transfer. In vivo expansion of transferred EBNA-1–specific T cells was observed in eight of 10 patients after a median of 16 days following adoptive transfer that was associated with clinical and virologic response in seven of them (70%). None of the responders had EBV-associated mortality. Within clinical responders, three patients were disease free by the day of last follow-up (2 to 36 months), three patients died of other infectious complications, and one patient died as a result of relapse of malignancy. EBV-related mortality was observed in two of 10 patients, and another patient had ongoing viremia without clinical symptoms at last follow-up. Conclusion Adoptive ex vivo transfer of EBNA-1–specific T cells is a feasible and well-tolerated therapeutic option, representing a fast and efficient procedure to achieve reconstitution of antiviral T-cell immunity after SCT.

Reconstitution of the Epstein-Barr virus–specific cytotoxic T-lymphocyte response following T-cell–depleted myeloablative and nonmyeloablative allogeneic stem cell transplantation

Blood ◽  
2003 ◽  
Vol 102 (3) ◽  
pp. 839-842 ◽  
Author(s):  
Suparno Chakrabarti ◽  
Donald W. Milligan ◽  
Deenan Pillay ◽  
Stephen Mackinnon ◽  
Kathleen Holder ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Epstein Barr Virus ◽  
Specific Response ◽  
Virus Infections ◽  
Barr Virus ◽  
Cell Immunity ◽  
Epstein Barr

AbstractThe recovery of circulating antigen-specific T-cell immunity to Epstein-Barr virus (EBV) was determined in ELIspot assays following allogeneic myeloablative or nonmyeloablative stem cell transplantation (MST/NST). In 8 of 12 MST patients receiving an alemtuzumab-treated graft, the frequency of the EBV-specific reactivities was similar to or greater than that seen in the healthy controls. A response was detectable in 3 of 6 and 6 of 9 patients by 3 and 6 months, respectively, and in all patients by one year following MST. In contrast, only 1 of 9 (95% confidence interval [CI], 0-2.8) patients made a detectable EBV-specific response by 6 months following NST conditioned with fludarabine, melphalan, and alemtuzumab. Responses were detected in 7 of 10 patients by 1 year after NST. Parallel surveillance demonstrated that other virus infections occurred more frequently and earlier after transplantation in NST patients. The use of alemtuzumab in vivo in the nonmyeloablative conditioning might have resulted in the delay in EBV-specific T-cell recovery and increased virus infections.

scholarly journals Co-Reactivation of Cytomegalovirus and Epstein-Barr Virus Was Associated With Poor Prognosis After Allogeneic Stem Cell Transplantation

2021 ◽  
Vol 11 ◽  
Author(s):  
Jing-Rui Zhou ◽  
Da-Yu Shi ◽  
Rong Wei ◽  
Yu Wang ◽  
Chen-Hua Yan ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Poor Prognosis ◽  
Epstein Barr Virus ◽  
Post Transplantation ◽  
Barr Virus ◽  
Epstein Barr ◽  
The Impact

Reactivation of cytomegalovirus (CMV) or Epstein-Barr virus (EBV) is common after hematopoietic stem cell transplantation (HSCT). Previous researches have demonstrated that either CMV or EBV reactivation is associated with poor outcomes of HSCT. However, few studies investigate the impact of CMV and EBV co-reactivation after HSCT. In this study, we described the clinical characteristics of HSCT recipients with CMV and EBV co-reactivation (defined as CMV and EBV viremia occur at the same period of time). We conducted a longitudinal study of 247 patients who underwent HSCT in our center. A total of 24 (9.7%) patients had CMV and EBV co-reactivation. These patients showed higher incidence of viral pneumonitis (P=0.005). Patients with CMV and EBV co-reactivation had significant lower 1-year overall survival (OS) (P=0.004) and lower 1-year leukemia free survival (LFS) (P=0.016). Our further analysis suggested that duration of CMV (P=0.014), EBV (P<0.001), and CD4+CD25+ T cell counts at day 30 post-transplantation (P=0.05) are independent risk factors of virus co-reactivation. In conclusion, patients who developed co-reactivation of CMV and EBV had poor prognosis in terms of lower 1-year OS and LFS, and the CMV and EBV co-reactivation was associated with prolonged CMV or EBV duration and poor CD4+CD25+ T cell reconstitution at day 30 post-transplantation.

scholarly journals The Outcomes of Epstein-Barr Virus Specific T Cells from Different Sources for EBV Infections in Recipients of Allogeneic Stem Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3330-3330
Author(s):  
Ren Lin ◽  
Fen Huang ◽  
Zhiping Fan ◽  
Xiaoyan Shao ◽  
Guoxian Dai ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Natural Science ◽  
Epstein Barr Virus ◽  
Third Party ◽  
Barr Virus ◽  
Ifn Γ ◽  
Epstein Barr

Abstract Background Epstein-Barr virus (EBV) specific T cells have been proven effective in prevention and treatment of EBV associated-diseases after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the optimal source of EBV specific T cells remains unclear. Here, we compared autologous and donor derived EBV specific T cells with respect to generation ex vivo and the efficacy on EBV infections in the recipients of allo-HSCT. Methods Thirty-eight patients with EBV infections were enrolled in this study, including 21 with EBV-emia and 17 with EBV associated post-transplant lymphoproliferative disease (PTLD). EBV specific T cells were generated by immunomagnetic isolation from all the recipients themselves and second-party (original HSCT donor, n=25) or third-party related donors (n=25). The donors were EBV seropositive. The percentages of IFN-γ+ EBV specific T cells in the products and cytotoxic capacity of EBV specific T cells were evaluated. Results The median time of EBV infections was 49 days (range, 24-1479 days) post-transplants. The generation of autologous EBV specific T cells failed within 14 days of culture in all the patients because the numbers of cells were insufficient for treatment. Donor derived EBV specific T cells were expanded in vitro for 14 days until the sufficient number (≥ 109) was generated. The percentages of IFN-γ+ EBV specific T cells were comparable in the products generated from second- and third-party donors, but both higher than autologous derived EBV specific T cells. Cytotoxic capacity of EBV specific T cells was lower in autologous EBV specific T cells than donor derived EBV specific T cells. Twenty-one patients with refractory EBV infections (12 with EBV-emia and 9 with PTLD) received EBV specific T cells treatment, including 13 receiving second-party and 8 third-party EBV specific T cells. After treatments, 20 patients exhibited EBV clearance in blood within 6 weeks without recurrence and 1 with PTLD died at 3 weeks after the first infusion of EBV specific T cells with the decline of EBV-DNA copies. Other 8 patients with PTLD received complete remission after treatment. The response rates were not different between the patients receiving second- and third-party donor derived EBV specific T cells. One of the 13 patients with second-party derived EBV specific T cells developed pre-existing chronic graft-versus-host disease (GVHD) exacerbation while 1 developed grade Ⅱ aGVHD in the 8 patients receiving third-party donor derived EBV specific T cells. Conclusion The efficacy of EBV-specific T cells derived from second- and third-party are comparable in treatment of EBV infections after allo-HSCT. Autologous derived EBV-specific T cells seems not suitable for treatment because of poor production in vitro. Disclosures Fan: National Natural Science Foundation of China (No. 81600141, No. 81770190) and Natural Science Foundation of Guangdong Province (No. 2016A030310390): Research Funding.

scholarly journals Epstein-Barr virus (EBV) reactivation is a frequent event after allogeneic stem cell transplantation (SCT) and quantitatively predicts EBV-lymphoproliferative disease following T-cell–depleted SCT

Blood ◽  
2001 ◽  
Vol 98 (4) ◽  
pp. 972-978 ◽  
Author(s):  
Joost W. J. van Esser ◽  
Bronno van der Holt ◽  
Ellen Meijer ◽  
Hubert G. M. Niesters ◽  
Rudolf Trenschel ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Epstein Barr Virus ◽  
Lymphoproliferative Disease ◽  
Viral Reactivation ◽  
Barr Virus ◽  
Ebv Reactivation ◽  
Epstein Barr

Reactivation of the Epstein-Barr virus (EBV) after allogeneic stem cell transplantation (allo-SCT) may evoke a protective cellular immune response or may be complicated by the development of EBV-lymphoproliferative disease (EBV-LPD). So far, very little is known about the incidence, recurrence, and sequelae of EBV reactivation following allo-SCT. EBV reactivation was retrospectively monitored in 85 EBV-seropositive recipients of a T-cell–depleted (TCD) allo-SCT and 65 EBV-seropositive recipients of an unmanipulated allo-SCT. Viral reactivation (more than 50 EBV genome equivalents [gEq]/mL) was monitored frequently by quantitative real-time plasma polymerase chain reaction until day 180 after SCT. Probabilities of developing viral reactivation were high after both unmanipulated and TCD-allogeneic SCT (31% ± 6% versus 65% ± 7%, respectively). A high CD34+ cell number of the graft appeared as a novel significant predictor (P = .001) for EBV reactivation. Recurrent reactivation was observed more frequently in recipients of a TCD graft, and EBV-LPD occurred only after TCD-SCT. High-risk status, TCD, and use of antithymocyte globulin were predictive for developing EBV-LPD. Plasma EBV DNA quantitatively predicted EBV-LPD. The positive and negative predictive values of a viral load of 1000 gEq/mL were, respectively, 39% and 100% after TCD. Treatment-related mortality did not differ significantly between TCD and non-TCD transplants, but the incidence of chronic graft-versus-host disease was significantly less in TCD patients. It is concluded that EBV reactivation occurs frequently after TCD and unmanipulated allo-SCT, especially in recipients of grafts with high CD34+ cell counts. EBV-LPD, however, occurred only after TCD, and EBV load quantitatively predicted EBV-LPD in recipients of a TCD graft.

scholarly journals Direct Visualization of Antigen-specific CD8+T Cells during the Primary Immune Response to Epstein-Barr Virus In Vivo

1998 ◽  
Vol 187 (9) ◽  
pp. 1395-1402 ◽  
Author(s):  
M.F.C. Callan ◽  
L. Tan ◽  
N. Annels ◽  
G.S. Ogg ◽  
J.D.K. Wilson ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Epstein Barr Virus ◽  
T Cell Response ◽  
Primary Immune Response ◽  
Barr Virus ◽  
Epstein Barr

Primary infection with virus can stimulate a vigorous cytotoxic T cell response. The magnitude of the antigen-specific component versus the bystander component of a primary T cell response remains controversial. In this study, we have used tetrameric major histocompatibility complex–peptide complexes to directly visualize antigen-specific cluster of differentration (CD)8+ T cells during the primary immune response to Epstein-Barr virus (EBV) infection in humans. We show that massive expansion of activated, antigen-specific T cells occurs during the primary response to this virus. In one individual, T cells specific for a single EBV epitope comprised 44% of the total CD8+ T cells within peripheral blood. The majority of the antigen-specific cells had an activated/memory phenotype, with expression of human histocompatibility leukocyte antigen (HLA) DR, CD38, and CD45RO, downregulation of CD62 leukocyte (CD62L), and low levels of expression of CD45RA. After recovery from AIM, the frequency of antigen-specific T cells fell in most donors studied, although populations of antigen-specific cells continued to be easily detectable for at least 3 yr.

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