Generation of Epstein-Barr virus–specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus (FK506)
Open Access
- 26 November 2009
- journal article
- Published by American Society of Hematology in Blood
- Vol. 114 (23), 4784-4791
- https://doi.org/10.1182/blood-2009-07-230482
Abstract
Adoptive transfer of autologous Epstein-Barr virus–specific cytotoxic T lymphocytes (EBV-CTLs) to solid organ transplant (SOT) recipients has been shown safe and effective for the treatment of EBV-associated posttransplantation lymphoproliferative disorders (PTLDs). SOT recipients, however, require the continuous administration of immunosuppressive drugs to prevent graft rejection, and these agents may significantly limit the long-term persistence of transferred EBV-CTLs, precluding their use as prophylaxis. Tacrolimus (FK506) is one of the most widely used immunosuppressive agents in SOT recipients, and its immunosuppressive effects are largely dependent on its interaction with the 12-kDa FK506-binding protein (FKBP12). We have knocked down the expression of FKBP12 in EBV-CTLs using a specific small interfering RNA (siRNA) stably expressed from a retroviral vector and found that FKBP12-silenced EBV-CTLs are FK506 resistant. These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity. We confirmed their FK506 resistance and anti-PTLD activity in vivo using a xenogenic mouse model, suggesting that the proposed strategy may be of value to enhance EBV-specific immune surveillance in patients at high risk of PTLD after transplantation.Keywords
This publication has 40 references indexed in Scilit:
- T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor modelBlood, 2009
- Genetic Manipulation of Tumor-specific Cytotoxic T Lymphocytes to Restore Responsiveness to IL-7Molecular Therapy, 2009
- Co-expression of cytokine and suicide genes to enhance the activity and safety of tumor-specific cytotoxic T lymphocytesBlood, 2007
- Epstein Barr virus–specific cytotoxic T lymphocytes expressing the anti-CD30ζ artificial chimeric T-cell receptor for immunotherapy of Hodgkin diseaseBlood, 2007
- Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trialBlood, 2007
- T lymphocytes redirected against the κ light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cellsBlood, 2006
- Treatment of solid organ transplant recipients with autologous Epstein Barr virus–specific cytotoxic T lymphocytes (CTLs)Blood, 2006
- Structures of calcineurin and its complexes with immunophilins–immunosuppressantsBiochemical and Biophysical Research Communications, 2003
- Treatment of Epstein-Barr-virus-positive post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cellsThe Lancet, 2002
- Role of Cytotoxic T Lymphocytes in Epstein-Barr Virus-Associated DiseasesAnnual Review of Microbiology, 2000