Interleukin-2-stimulated natural killer cells are less susceptible to mycophenolate mofetil than non-activated NK cells: possible consequences for immunotherapy

被引:27
作者
Brehm, Claudia [1 ]
Huenecke, Sabine [1 ]
Esser, Ruth [2 ]
Kloess, Stephan [2 ]
Quaiser, Andrea [1 ]
Betz, Sibille [1 ]
Zimmermann, Olga [1 ]
Soerensen, Jan [1 ]
Passweg, Jakob R. [3 ]
Klingebiel, Thomas [1 ]
Schwabe, Dirk [1 ]
Bader, Peter [1 ]
Koehl, Ulrike [2 ]
机构
[1] Goethe Univ Frankfurt, Clin Pediat & dolescent Med, Univ Hosp Frankfurt, D-60054 Frankfurt, Germany
[2] Hannover Med Sch, Inst Cellular Therapeut, GMP Dev Unit, IFB Tx & Cellular Therapy Ctr, Hannover, Germany
[3] Univ Basel Hosp, Dept Hematol, CH-4031 Basel, Switzerland
关键词
MMF; MPA; NK cells; Immunosuppressive therapy; Immunotherapy; Haploidentical stem cell transplantation; IN-VIVO; T-CELLS; TRANSPLANTATION; CYTOTOXICITY; RECEPTORS; MECHANISMS; CANCER; BIOLOGY; KINASE; IL-2;
D O I
10.1007/s00262-014-1556-5
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
In a clinical phase I/II trial, pediatric patients with high-risk malignancies were treated with ex vivo IL-2-stimulated donor natural killer (NK) cells after transplantation with haploidentical stem cells. To evaluate the potential negative effects of the immunosuppressive drug mycophenolate mofetil (MMF) used for immunotherapy, the functionality and signaling of ex vivo NK cells was investigated. Our results show that during NK cell expansion, long-term (9 days) incubation with mycophenolic acid (MPA), the active metabolite of MMF, in therapeutically relevant concentrations led to the severe inhibition of NK cell proliferation. This correlated with a significantly reduced cytokine/chemokine secretion and the inhibited acquisition of surface receptors regarding cytotoxicity (e.g., NKp30, NKp44, NKp46, NKG2D), adhesion/migration (e.g., ICAM-1/CD54, LFA-1/CD11a, CD62L, CXCR3) and activation (e.g., CD25). Moreover, MPA prevented phosphorylation of the central signaling molecules STAT-3/-4/-5, AKT and ERK1/2. In contrast, short-term (24 h) MPA incubation of IL-2-stimulated NK cells had no or only marginal effects on the activated NK cell phenotype, including receptor expression, cytokine/chemokine secretion and intracellular signaling. Further, short-term MPA incubation only moderately affected the highly cytotoxic activity of previously IL-2-stimulated NK cells. In conclusion, while long-term MPA incubation significantly compromised ex vivo NK cell functionality, previously IL-2-activated NK cells seemed to be rather resistant to short-term MPA treatment. This finding supports the use of IL-2-activated NK cells as immunotherapy, especially for patients treated with MMF after haploidentical stem cell transplantation.
引用
收藏
页码:821 / 833
页数:13
相关论文
共 44 条
[1]   Mechanisms of action of mycophenolate mofetil in preventing acute and chronic allograft rejection [J].
Allison, AC ;
Eugui, EM .
TRANSPLANTATION, 2005, 80 (02) :S181-S190
[2]   IMMUNOSUPPRESSIVE AND OTHER EFFECTS OF MYCOPHENOLIC-ACID AND AN ESTER PRODRUG, MYCOPHENOLATE MOFETIL [J].
ALLISON, AC ;
EUGUI, EM .
IMMUNOLOGICAL REVIEWS, 1993, 136 :5-28
[3]  
ALLISON AC, 1993, ANN NY ACAD SCI, V696, P63
[4]   Mycophenolate mofetil and its mechanisms of action [J].
Allison, AC ;
Eugui, EM .
IMMUNOPHARMACOLOGY, 2000, 47 (2-3) :85-118
[5]   Novel assays of multiple lymphocyte functions in whole blood measure - New mechanisms of action of mycophenolate mofetil in vivo [J].
Barten, MJ ;
van Gelder, T ;
Gummert, JF ;
Shorthouse, R ;
Morris, RE .
TRANSPLANT IMMUNOLOGY, 2002, 10 (01) :1-14
[6]   Graft-versus-host disease - Mycophenolate mofetil for the treatment of acute and chronic GVHD is effective and well tolerated but induces a high risk of infectious complications: a series of 21 BM or PBSC transplant patients [J].
Baudard, M ;
Vincent, A ;
Moreau, P ;
Kergueris, MF ;
Harousseau, JL ;
Milpied, N .
BONE MARROW TRANSPLANTATION, 2002, 30 (05) :287-295
[7]   An Age-Dependent Pharmacokinetic Study of Intravenous and Oral Mycophenolate Mofetil in Combination with Tacrolimus for GVHD Prophylaxis in Pediatric Allogeneic Stem Cell Transplantation Recipients [J].
Bhatia, Monica ;
Militano, Olga ;
Jin, Zhezhen ;
Figurski, Michal ;
Shaw, Leslie ;
Moore, Virginia ;
Morris, Erin ;
Tallamy, Bradford ;
van deVen, Carmella ;
Ayello, Janet ;
Baxter-Lowe, LeeAnn ;
Satwani, Prakash ;
George, Diane ;
Bradley, M. Brigid ;
Garvin, James ;
Cairo, Mitchell S. .
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION, 2010, 16 (03) :333-343
[8]  
Biassoni Roberto, 2009, Curr Protoc Immunol, VChapter 14, DOI 10.1002/0471142735.im1410s84
[9]   Mycophenolate mofetil impairs transendothelial migration of allogeneic CD4 and CD8 T-cells [J].
Blaheta, RA ;
Leckel, K ;
Wittig, B ;
Zenker, D ;
Oppermann, E ;
Harder, S ;
Scholz, M ;
Weber, S ;
Encke, A ;
Markus, BH .
TRANSPLANTATION PROCEEDINGS, 1999, 31 (1-2) :1250-1252
[10]   IL-2 Stimulated but Not Unstimulated NK Cells Induce Selective Disappearance of Peripheral Blood Cells: Concomitant Results to a Phase I/II Study [J].
Brehm, Claudia ;
Huenecke, Sabine ;
Quaiser, Andrea ;
Esser, Ruth ;
Bremm, Melanie ;
Kloess, Stephan ;
Soerensen, Jan ;
Kreyenberg, Hermann ;
Seidl, Christian ;
Becker, Petra S. A. ;
Muehl, Heiko ;
Klingebiel, Thomas ;
Bader, Peter ;
Passweg, Jakob R. ;
Schwabe, Dirk ;
Koehl, Ulrike .
PLOS ONE, 2011, 6 (11)