Generation of Epstein-Barr virus-specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus (FK506)

Biagio De Angelis, Gianpietro Dotti, Concetta Quintarelli, Leslie E. Huye, Lan Zhang, Ming Zhang, Fabrizio Pane, Helen E. Heslop, Malcolm K. Brenner, Cliona M. Rooney, Barbara Savoldo

Research output: Contribution to journalArticle

64 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4784-4791
Number of pages8
JournalBlood
Volume114
Issue number23
DOIs
Publication statusPublished - Nov 26 2009

Fingerprint

T-cells
Tacrolimus Binding Protein 1A
Cytotoxic T-Lymphocytes
Tacrolimus
Immunosuppressive Agents
Human Herpesvirus 4
Viruses
Transplants
Lymphoproliferative Disorders
Pharmaceutical Preparations
Tacrolimus Binding Proteins
Grafts
Small Interfering RNA
Adoptive Transfer
Graft Rejection
Antigens
Transplantation
Transplant Recipients

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Generation of Epstein-Barr virus-specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus (FK506). / De Angelis, Biagio; Dotti, Gianpietro; Quintarelli, Concetta; Huye, Leslie E.; Zhang, Lan; Zhang, Ming; Pane, Fabrizio; Heslop, Helen E.; Brenner, Malcolm K.; Rooney, Cliona M.; Savoldo, Barbara.

In: Blood, Vol. 114, No. 23, 26.11.2009, p. 4784-4791.

Research output: Contribution to journalArticle

De Angelis, B, Dotti, G, Quintarelli, C, Huye, LE, Zhang, L, Zhang, M, Pane, F, Heslop, HE, Brenner, MK, Rooney, CM & Savoldo, B 2009, 'Generation of Epstein-Barr virus-specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus (FK506)', Blood, vol. 114, no. 23, pp. 4784-4791. https://doi.org/10.1182/blood-2009-07-230482
De Angelis, Biagio ; Dotti, Gianpietro ; Quintarelli, Concetta ; Huye, Leslie E. ; Zhang, Lan ; Zhang, Ming ; Pane, Fabrizio ; Heslop, Helen E. ; Brenner, Malcolm K. ; Rooney, Cliona M. ; Savoldo, Barbara. / Generation of Epstein-Barr virus-specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus (FK506). In: Blood. 2009 ; Vol. 114, No. 23. pp. 4784-4791.
@article{346051c7a1dc4e70bd4984a73e1c7cb3,
title = "Generation of Epstein-Barr virus-specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus (FK506)",
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.",
author = "{De Angelis}, Biagio and Gianpietro Dotti and Concetta Quintarelli and Huye, {Leslie E.} and Lan Zhang and Ming Zhang and Fabrizio Pane and Heslop, {Helen E.} and Brenner, {Malcolm K.} and Rooney, {Cliona M.} and Barbara Savoldo",
year = "2009",
month = "11",
day = "26",
doi = "10.1182/blood-2009-07-230482",
language = "English",
volume = "114",
pages = "4784--4791",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "23",

}

TY - JOUR

T1 - Generation of Epstein-Barr virus-specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus (FK506)

AU - De Angelis, Biagio

AU - Dotti, Gianpietro

AU - Quintarelli, Concetta

AU - Huye, Leslie E.

AU - Zhang, Lan

AU - Zhang, Ming

AU - Pane, Fabrizio

AU - Heslop, Helen E.

AU - Brenner, Malcolm K.

AU - Rooney, Cliona M.

AU - Savoldo, Barbara

PY - 2009/11/26

Y1 - 2009/11/26

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=73449085640&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=73449085640&partnerID=8YFLogxK

U2 - 10.1182/blood-2009-07-230482

DO - 10.1182/blood-2009-07-230482

M3 - Article

VL - 114

SP - 4784

EP - 4791

JO - Blood

JF - Blood

SN - 0006-4971

IS - 23

ER -