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



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.



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.



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.
Clinic for Pediatric and Adolescent Medicine, University Hospital, Theodor-Stern-Kai 7, 60596, Frankfurt/Main, Germany. melanie.bremm@kgu.de.
Melanie
M
Bremm
Clinic for Pediatric and Adolescent Medicine, University Hospital, Theodor-Stern-Kai 7, 60596, Frankfurt/Main, Germany.
Sabine
S
Huenecke
Clinic for Pediatric and Adolescent Medicine, University Hospital, Theodor-Stern-Kai 7, 60596, Frankfurt/Main, Germany.
Olga
O
Zimmermann
Clinic for Pediatric and Adolescent Medicine, University Hospital, Theodor-Stern-Kai 7, 60596, Frankfurt/Main, Germany.
Verena
V
Pfirrmann
Clinic for Pediatric and Adolescent Medicine, University Hospital, Theodor-Stern-Kai 7, 60596, Frankfurt/Main, Germany.
Andrea
A
Quaiser
Division for Translational Development of Cellular Therapeutics, Institute for Transfusion Medicine and Immunohematology, Goethe-University Frankfurt/Main, Frankfurt/Main, Germany.|German Red Cross Blood Donor Service Baden-Württemberg-Hessen, Frankfurt/Main, Germany.
Halvard
H
Bonig
Clinic for Pediatric and Adolescent Medicine, University Hospital, Theodor-Stern-Kai 7, 60596, Frankfurt/Main, Germany.
Jan
J
Soerensen
Clinic for Pediatric and Adolescent Medicine, University Hospital, Theodor-Stern-Kai 7, 60596, Frankfurt/Main, Germany.
Thomas
T
Klingebiel
Clinic for Pediatric and Adolescent Medicine, University Hospital, Theodor-Stern-Kai 7, 60596, Frankfurt/Main, Germany.
Eva
E
Rettinger
Clinic for Pediatric and Adolescent Medicine, University Hospital, Theodor-Stern-Kai 7, 60596, Frankfurt/Main, Germany.
Peter
P
Bader
Clinic for Pediatric and Adolescent Medicine, University Hospital, Theodor-Stern-Kai 7, 60596, Frankfurt/Main, Germany.
Claudia
C
Cappel
D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D055612:Cytokine-Induced Killer Cells / Q000187:drug effects / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006801:Humans; D007167:Immunotherapy; D009173:Mycophenolic Acid / Q000494:pharmacology*
D016207:Cytokines; D016572:Cyclosporine; D009173:Mycophenolic Acid
Allogeneic stem cell transplantation; CIK cells; Immunosuppressive therapy; Immunotherapy; MMF; MPA