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Rapid Generation of EBV-Specific Cytotoxic T Lymphocytes Resistant to Calcineurin Inhibitors for Adoptive Immunotherapy.

Ricciardelli, I; Brewin, J; Lugthart, G; Albon, SJ; Pule, M; Amrolia, PJ; (2013) Rapid Generation of EBV-Specific Cytotoxic T Lymphocytes Resistant to Calcineurin Inhibitors for Adoptive Immunotherapy. Am J Transplant , 13 (12) 3244 - 3252. 10.1111/ajt.12475. Green open access

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Abstract

Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder (PTLD) remains a major cause of morbidity and mortality after hematopoietic stem cell (HSCT) or solid organ transplant (SOT). Strategies to reconstitute immunity by adoptive transfer of EBV-specific cytotoxic T lymphocyte (CTL) therapy while highly effective in the HSCT setting where immunosuppression can be withdrawn have been less successful in the SOT setting where continued immunosuppression therapy is necessary. Additionally, the complexity and time taken to generate EBV-CTLs for adoptive transfer limit the clinical applicability. We have developed a system for the rapid generation of EBV-CTLs resistant to immunosuppression based on selection of interferon-gamma (IFN-γ) secreting EBV-CTLs and retroviral transduction with a calcineurin B mutant. With this methodology, EBV-CTLs resistant to the calcineurin inhibitor Tacrolimus (TAC) can be produced in 14 days. These CTLs show high specificity for EBV with negligible alloreactivity in both proliferation and cytotoxicity assays and are able to proliferate and secrete IFN-γ in response to antigen stimulation in the presence of therapeutic doses of TAC. This strategy will substantially facilitate clinical application of this approach for the treatment of PTLD in SOT recipients.

Type: Article
Title: Rapid Generation of EBV-Specific Cytotoxic T Lymphocytes Resistant to Calcineurin Inhibitors for Adoptive Immunotherapy.
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/ajt.12475
Publisher version: http://dx.doi.org/10.1111/ajt.12475
Language: English
Additional information: �© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons. Full text made available to UCL Discovery by kind permission of Wiley.
Keywords: Calcineurin inhibitors resistance, Epstein-Barr virus, IFN-γ selection, cytotoxic T lymphocytes, posttransplant lymphoma, solid organ transplant
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health > ICH Infect, Imm, Infla. and Physio Med
URI: http://discovery.ucl.ac.uk/id/eprint/1422636
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