In-vitro influence of mycophenolate mofetil MMF and Ciclosporin A CsA on cytokine induced killer CIK cell immunotherapyReport as inadecuate




In-vitro influence of mycophenolate mofetil MMF and Ciclosporin A CsA on cytokine induced killer CIK cell immunotherapy - Download this document for free, or read online. Document in PDF available to download.

Journal of Translational Medicine

, 14:264

Immunobiology andimmunotherapy

Abstract

BackgroundCytokine-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.

MethodsCIK 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.

ResultsShort-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. CD3CD56 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.

ConclusionsOur 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.

KeywordsMMF MPA CIK cells Immunosuppressive therapy Immunotherapy Allogeneic stem cell transplantation AbbreviationsAPCallophycocyanin

APC-A700APC-Alexa Fluor 700

APC-A750APC-Alexa Fluor 750

CIKcytokine-induced killer

CsACiclosporin A

FITCfluorescein–isothiocyanate

ECDphycoerythrin-Texas Red

GvL-Tgraft-versus-leukemia-tumor

DLIdonor lymphocyte infusion

GvHDgraft-versus-host disease

GMPgood manufacturing practice

HSCThematopoietic stem cell transplantation

KOkrome orange

MMFmycophenolate mofetil

MPAmycophenolic acid

MRDminimal residual disease

NKnatural killer

PBMCperipheral blood mononuclear cells

PBpacific blue™

PC-5phycoerythrin–cyanine-5

PC-7phycoerythrin–cyanine-7

PEphycoerythrin

Melanie Bremm and Sabine Huenecke contributed equally to this work

Electronic supplementary materialThe online version of this article doi:10.1186-s12967-016-1024-4 contains supplementary material, which is available to authorized users.





Author: Melanie Bremm - Sabine Huenecke - Olga Zimmermann - Verena Pfirrmann - Andrea Quaiser - Halvard Bonig - Jan Soerensen - Tho

Source: https://link.springer.com/







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