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In-vitro influence of mycophenolate mofetil (MMF) and Ciclosporin A (CsA) on cytokine induced killer (CIK) cell immunotherapy

BACKGROUND: Cytokine-induced-killer (CIK) cells are a promising immunotherapeutic approach for impending relapse following hematopoietic stem cell transplantation (HSCT). However, there is a high risk for treatment failure associated with severe graft versus host disease (GvHD) necessitating pharmac...

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Autores principales: Bremm, Melanie, Huenecke, Sabine, Zimmermann, Olga, Pfirrmann, Verena, Quaiser, Andrea, Bonig, Halvard, Soerensen, Jan, Klingebiel, Thomas, Rettinger, Eva, Bader, Peter, Cappel, Claudia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5020454/
https://www.ncbi.nlm.nih.gov/pubmed/27620209
http://dx.doi.org/10.1186/s12967-016-1024-4
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author Bremm, Melanie
Huenecke, Sabine
Zimmermann, Olga
Pfirrmann, Verena
Quaiser, Andrea
Bonig, Halvard
Soerensen, Jan
Klingebiel, Thomas
Rettinger, Eva
Bader, Peter
Cappel, Claudia
author_facet Bremm, Melanie
Huenecke, Sabine
Zimmermann, Olga
Pfirrmann, Verena
Quaiser, Andrea
Bonig, Halvard
Soerensen, Jan
Klingebiel, Thomas
Rettinger, Eva
Bader, Peter
Cappel, Claudia
author_sort Bremm, Melanie
collection PubMed
description BACKGROUND: Cytokine-induced-killer (CIK) cells are a promising immunotherapeutic approach for impending relapse following hematopoietic stem cell transplantation (HSCT). However, there is a high risk for treatment failure associated with severe graft versus host disease (GvHD) necessitating pharmaceutical intervention post-transplant. Whether immunosuppression with mycophenolate mofetil (MMF) or Ciclosporin A (CsA) influences the cytotoxic effect of CIK cell immunotherapy is still an open issue. METHODS: CIK cells were generated from PBMC as previously described followed by co-incubation with mycophenolic acid (MPA) or CsA. Proliferation, cytotoxicity and receptor expression were investigated following short- (24 h), intermediate- (3 days) and long-term (7 days) MPA incubation with the intention to simulate the in vivo situation when CIK cells were given to a patient with relevant MPA/CsA plasma levels. RESULTS: Short-term MPA treatment led to unchanged proliferation capacity and barely had any effect on viability and cytotoxic capability in vitro. The composition of CIK cells with respect to T-, NK-like T- and NK cells remained stable. Intermediate MPA treatment lacked effects on NKG2D, FasL and TRAIL receptor expression, while an influence on proliferation and viability was detectable. Furthermore, long-term treatment significantly impaired proliferation, restricted viability and drastically reduced migration-relevant receptors accompanied by an alteration in the CD4/CD8 ratio. CD3(+)CD56(+) cells upregulated receptors relevant for CIK cell killing and migration, whereas T cells showed the most interference through significant reductions in receptor expression. Interestingly, CsA treatment had no significant influence on CIK cell viability and the cytotoxic potential against K562. CONCLUSIONS: Our data indicate that if immunosuppressant therapy is indispensable, efficacy of CIK cells is maintained at least short-term, although more frequent dosing might be necessary. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12967-016-1024-4) contains supplementary material, which is available to authorized users.
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spelling pubmed-50204542016-09-14 In-vitro influence of mycophenolate mofetil (MMF) and Ciclosporin A (CsA) on cytokine induced killer (CIK) cell immunotherapy Bremm, Melanie Huenecke, Sabine Zimmermann, Olga Pfirrmann, Verena Quaiser, Andrea Bonig, Halvard Soerensen, Jan Klingebiel, Thomas Rettinger, Eva Bader, Peter Cappel, Claudia J Transl Med Research BACKGROUND: Cytokine-induced-killer (CIK) cells are a promising immunotherapeutic approach for impending relapse following hematopoietic stem cell transplantation (HSCT). However, there is a high risk for treatment failure associated with severe graft versus host disease (GvHD) necessitating pharmaceutical intervention post-transplant. Whether immunosuppression with mycophenolate mofetil (MMF) or Ciclosporin A (CsA) influences the cytotoxic effect of CIK cell immunotherapy is still an open issue. METHODS: CIK cells were generated from PBMC as previously described followed by co-incubation with mycophenolic acid (MPA) or CsA. Proliferation, cytotoxicity and receptor expression were investigated following short- (24 h), intermediate- (3 days) and long-term (7 days) MPA incubation with the intention to simulate the in vivo situation when CIK cells were given to a patient with relevant MPA/CsA plasma levels. RESULTS: Short-term MPA treatment led to unchanged proliferation capacity and barely had any effect on viability and cytotoxic capability in vitro. The composition of CIK cells with respect to T-, NK-like T- and NK cells remained stable. Intermediate MPA treatment lacked effects on NKG2D, FasL and TRAIL receptor expression, while an influence on proliferation and viability was detectable. Furthermore, long-term treatment significantly impaired proliferation, restricted viability and drastically reduced migration-relevant receptors accompanied by an alteration in the CD4/CD8 ratio. CD3(+)CD56(+) cells upregulated receptors relevant for CIK cell killing and migration, whereas T cells showed the most interference through significant reductions in receptor expression. Interestingly, CsA treatment had no significant influence on CIK cell viability and the cytotoxic potential against K562. CONCLUSIONS: Our data indicate that if immunosuppressant therapy is indispensable, efficacy of CIK cells is maintained at least short-term, although more frequent dosing might be necessary. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12967-016-1024-4) contains supplementary material, which is available to authorized users. BioMed Central 2016-09-13 /pmc/articles/PMC5020454/ /pubmed/27620209 http://dx.doi.org/10.1186/s12967-016-1024-4 Text en © The Author(s) 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Bremm, Melanie
Huenecke, Sabine
Zimmermann, Olga
Pfirrmann, Verena
Quaiser, Andrea
Bonig, Halvard
Soerensen, Jan
Klingebiel, Thomas
Rettinger, Eva
Bader, Peter
Cappel, Claudia
In-vitro influence of mycophenolate mofetil (MMF) and Ciclosporin A (CsA) on cytokine induced killer (CIK) cell immunotherapy
title In-vitro influence of mycophenolate mofetil (MMF) and Ciclosporin A (CsA) on cytokine induced killer (CIK) cell immunotherapy
title_full In-vitro influence of mycophenolate mofetil (MMF) and Ciclosporin A (CsA) on cytokine induced killer (CIK) cell immunotherapy
title_fullStr In-vitro influence of mycophenolate mofetil (MMF) and Ciclosporin A (CsA) on cytokine induced killer (CIK) cell immunotherapy
title_full_unstemmed In-vitro influence of mycophenolate mofetil (MMF) and Ciclosporin A (CsA) on cytokine induced killer (CIK) cell immunotherapy
title_short In-vitro influence of mycophenolate mofetil (MMF) and Ciclosporin A (CsA) on cytokine induced killer (CIK) cell immunotherapy
title_sort in-vitro influence of mycophenolate mofetil (mmf) and ciclosporin a (csa) on cytokine induced killer (cik) cell immunotherapy
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5020454/
https://www.ncbi.nlm.nih.gov/pubmed/27620209
http://dx.doi.org/10.1186/s12967-016-1024-4
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