{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T23:45:36Z","timestamp":1768434336425,"version":"3.49.0"},"reference-count":40,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2019,11,19]],"date-time":"2019-11-19T00:00:00Z","timestamp":1574121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005564","name":"Gilead Sciences","doi-asserted-by":"publisher","award":["unrestricted grant"],"award-info":[{"award-number":["unrestricted grant"]}],"id":[{"id":"10.13039\/100005564","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>As the prognosis of invasive aspergillosis remains unacceptably poor in patients undergoing hematopoietic stem cell transplantation (HSCT), there is a growing interest in the adoptive transfer of antifungal effector cells, such as Natural Killer (NK) cells. Because immunosuppressive agents are required in most HSCT recipients, knowledge of the impact of these compounds on the antifungal activity of NK cells is a prerequisite for clinical trials. We, therefore, assessed the effect of methylprednisolone (mPRED), cyclosporin A (CsA) and mycophenolic acid (MPA) at different concentrations on proliferation, apoptosis\/necrosis, and the direct and indirect anti-Aspergillus activity of human NK cells. Methylprednisolone decreased proliferation and increased apoptosis of NK cells in a significant manner. After seven days, a reduction of viable NK cells was seen for all three immunosuppressants, which was significant for MPA only. Cyclosporin A significantly inhibited the direct hyphal damage by NK cells in a dose-dependent manner. None of the immunosuppressive compounds had a major impact on the measured levels of interferon-\u03b3, granulocyte-macrophage colony-stimulating factor and RANTES (regulated on activation, normal T cell expressed and secreted; CCL5). Our data demonstrate that commonly used immunosuppressive compounds have distinct effects on proliferation, viability and antifungal activity of human NK cells, which should be considered in designing studies on the use of NK cells for adoptive antifungal immunotherapy.<\/jats:p>","DOI":"10.3390\/pathogens8040246","type":"journal-article","created":{"date-parts":[[2019,11,19]],"date-time":"2019-11-19T11:30:17Z","timestamp":1574163017000},"page":"246","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Distinct Effects of Immunosuppressive Drugs on the Anti-Aspergillus Activity of Human Natural Killer Cells"],"prefix":"10.3390","volume":"8","author":[{"given":"Stanislaw","family":"Schmidt","sequence":"first","affiliation":[{"name":"Division of Pediatric Hematology and Oncology, Hospital for Children and Adolescents, University Hospital, Goethe University Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ralf","family":"Schubert","sequence":"additional","affiliation":[{"name":"Pediatric Pulmonology, Allergology and Cystic Fibrosis, Hospital for Children and Adolescents, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asuman","family":"Demir","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology and Oncology, Hospital for Children and Adolescents, University Hospital, Goethe University Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Lehrnbecher","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology and Oncology, Hospital for Children and Adolescents, University Hospital, Goethe University Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1086\/651263","article-title":"Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001\u20132006: Overview of the transplant-associated infection surveillance network (TRANSNET) database","volume":"50","author":"Kontoyiannis","year":"2010","journal-title":"Clin. Infect. Dis."},{"key":"ref_2","first-page":"1149","article-title":"Population-based analysis of invasive fungal infections","volume":"20","author":"Bitar","year":"2014","journal-title":"Emerg. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3689","DOI":"10.2174\/1381612811319200010","article-title":"Immunotherapy in invasive fungal infection\u2014Focus on invasive aspergillosis","volume":"19","author":"Lehrnbecher","year":"2013","journal-title":"Curr. Pharm. Des."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/nri2939","article-title":"Immunity to fungal infections","volume":"11","author":"Romani","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.3389\/fimmu.2017.01623","article-title":"Natural killer cells in antifungal immunity","volume":"8","author":"Schmidt","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1093\/infdis\/jiq062","article-title":"Human natural killer cells exhibit direct activity against Aspergillus fumigatus hyphae, but not against resting conidia","volume":"203","author":"Schmidt","year":"2011","journal-title":"J. Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.4049\/jimmunol.1003593","article-title":"Human NK cells display important antifungal activity against aspergillus fumigatus, which is directly mediated by IFN-\u03b3 release","volume":"187","author":"Bouzani","year":"2011","journal-title":"J. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1111\/myc.12431","article-title":"Natural killer cell-mediated damage of clinical isolates of mucormycetes","volume":"59","author":"Schmidt","year":"2016","journal-title":"Mycoses"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1093\/infdis\/jit574","article-title":"Human natural killer cells acting as phagocytes against Candida albicans and mounting an inflammatory response that modulates neutrophil antifungal activity","volume":"209","author":"Voigt","year":"2014","journal-title":"J. Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1093\/infdis\/jis308","article-title":"Characterization of the cellular immune responses to rhizopus oryzae with potential impact on immunotherapeutic strategies in hematopoietic stem cell transplantation","volume":"206","author":"Schmidt","year":"2012","journal-title":"J. Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1080\/02681219280000591","article-title":"Enhanced phagocytosis and intracellular killing of Candida albicans by GM-CSF-activated human neutrophils","volume":"30","author":"Richardson","year":"1992","journal-title":"J. Med. Vet. Mycol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1093\/infdis\/170.4.894","article-title":"Antifungal activity of elutriated human monocytes against Aspergillus fumigatus hyphae: Enhancement by granulocyte-macrophage colony-stimulating factor and interferon-gamma","volume":"170","author":"Roilides","year":"1994","journal-title":"J. Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/nri748","article-title":"Chemokines: Agents for the immunotherapy of cancer?","volume":"2","author":"Homey","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6138","DOI":"10.1038\/s41598-017-06238-4","article-title":"CD56 is a pathogen recognition receptor on human natural killer cells","volume":"7","author":"Ziegler","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4306","DOI":"10.4049\/jimmunol.0803462","article-title":"Early NK cell-derived IFN-y is essential to host defense in neutropenic invasive aspergillosis","volume":"182","author":"Park","year":"2009","journal-title":"J. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.1128\/AAC.48.5.1664-1669.2004","article-title":"In vitro interactions between antifungals and immunosuppressants against Aspergillus fumigatus","volume":"48","author":"Steinbach","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1093\/mmy\/myu034","article-title":"Methylprednisolone impairs conidial phagocytosis but does not attenuate hyphal damage by neutrophils against Exserohilum rostratum","volume":"53","author":"Simitsopoulou","year":"2015","journal-title":"Med. Mycol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1007\/s00262-011-1067-6","article-title":"Effect of the simultaneous administration of glucocorticoids and IL-15 on human NK cell phenotype, proliferation and function","volume":"60","author":"Moustaki","year":"2011","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1191\/0961203305LU2109OA","article-title":"Mechanisms of action of mycophenolate mofetil","volume":"14","author":"Allison","year":"2005","journal-title":"Lupus"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/S0162-3109(00)00192-2","article-title":"Mechanisms of action of cyclosporine","volume":"47","author":"Matsuda","year":"2000","journal-title":"Immunopharmacology"},{"key":"ref_21","first-page":"14","article-title":"Molecular analysis of the methylprednisolone-mediated inhibition of NK-cell function: Evidence for different susceptibility of IL-2\u2013versus IL-15\u2013activated NK cells","volume":"97","author":"Chiossone","year":"2007","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"556","DOI":"10.3389\/fimmu.2019.00556","article-title":"Small-molecule immunosuppressive drugs and therapeutic immunoglobulins differentially inhibit NK cell effector functions in vitro","volume":"10","author":"Pradier","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.chom.2013.09.007","article-title":"The NK receptor NKp30 mediates direct fungal recognition and killing and is diminished in NK cells from HIV-infected patients","volume":"14","author":"Li","year":"2013","journal-title":"Cell Host Microbe"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"750","DOI":"10.3389\/fmicb.2016.00750","article-title":"Candida albicans induces metabolic reprogramming in human NK cells and responds to perforin with a zinc depletion response","volume":"7","author":"Hellwig","year":"2016","journal-title":"Front. Microbiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3357","DOI":"10.4049\/jimmunol.173.5.3357","article-title":"NK cells use perforin rather than granulysin for anticryptococcal activity","volume":"173","author":"Ma","year":"2004","journal-title":"J. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/j.imbio.2012.10.013","article-title":"Rhizopus oryzae hyphae are damaged by human natural killer (NK) cells, but suppress NK cell mediated immunity","volume":"218","author":"Schmidt","year":"2013","journal-title":"Immunobiology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1007\/s00262-014-1556-5","article-title":"Interleukin-2-stimulated natural killer cells are less susceptible to mycophenolate mofetil than non-activated NK cells: Possible consequences for immunotherapy","volume":"63","author":"Brehm","year":"2014","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1016\/j.transproceed.2017.03.018","article-title":"Impact of steroids on natural killer cells against cytotoxicity and Hepatitis C Virus replication","volume":"49","author":"Ohira","year":"2017","journal-title":"Transplant. Proc."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.1080\/21505594.2017.1339007","article-title":"Treatment of Cyclosporin A retains host defense against invasive pulmonary aspergillosis in a non-immunosuppressive murine model by preserving the myeloid cell population","volume":"8","author":"Wong","year":"2017","journal-title":"Virulence"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.1182\/blood-2006-10-048173","article-title":"The unexpected effect of cyclosporin A on CD56+CD16\u2212 and CD56+CD16+ natural killer cell subpopulations","volume":"110","author":"Wang","year":"2007","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"432","DOI":"10.3389\/fimmu.2017.00432","article-title":"Distinct effects of dexamethasone on human natural killer cell responses dependent on cytokines","volume":"8","author":"Morgan","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"71062","DOI":"10.18632\/oncotarget.12616","article-title":"Aspergillus fumigatus responds to natural killer (NK) cells with upregulation of stress related genes and inhibits the immunoregulatory function of NK cells","volume":"7","author":"Schneider","year":"2016","journal-title":"Oncotarget"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1111\/j.1600-6143.2010.03242.x","article-title":"Rapamycin and MPA, but not CsA, impair human NK Cell cytotoxicity due to differential effects on NK cell phenotype","volume":"10","author":"Eissens","year":"2010","journal-title":"Am. J. Transplant."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Brehm, C., Huenecke, S., Quaiser, A., Esser, R., Bremm, M., Kloess, S., Soerensen, J., Kreyenberg, H., Seidl, C., and Becker, P.S.A. (2011). IL-2 stimulated but not unstimulated NK cells induce selective disappearance of peripheral blood cells: Concomitant results to a phase I\/II study. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0027351"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3051","DOI":"10.1182\/blood-2004-07-2974","article-title":"Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer","volume":"105","author":"Miller","year":"2005","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1016\/j.bbmt.2016.04.009","article-title":"Haploidentical natural killer cells infused before allogeneic stem cell transplantation for myeloid malignancies: A phase I trial","volume":"22","author":"Lee","year":"2016","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2649","DOI":"10.1128\/IAI.01700-14","article-title":"Immunosuppressive compounds exhibit particular effects on functional properties of human anti-aspergillus TH1 cells","volume":"82","author":"Tramsen","year":"2014","journal-title":"Infect. Immun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1097\/FTD.0b013e31815c12ca","article-title":"Achievement of target cyclosporine concentrations as a predictor of severe acute graft versus host disease in children undergoing hematopoietic stem cell transplantation and receiving cyclosporine and methotrexate prophylaxis","volume":"29","author":"Punnett","year":"2007","journal-title":"Ther. Drug Monit."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1002\/j.1552-4604.1997.tb04266.x","article-title":"Pharmacokinetics of methylprednisolone and prednisolone after single and multiple oral administration","volume":"37","author":"Rohatagi","year":"1997","journal-title":"J. Clin. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.bbmt.2003.11.005","article-title":"A pilot study of tacrolimus and mycophenolate mofetil graft-versus-host disease prophylaxis in childhood and adolescent allogeneic stem cell transplant recipients","volume":"10","author":"Osunkwo","year":"2004","journal-title":"Biol. Blood Marrow Transplant."}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/8\/4\/246\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:35:43Z","timestamp":1760189743000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/8\/4\/246"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,19]]},"references-count":40,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["pathogens8040246"],"URL":"https:\/\/doi.org\/10.3390\/pathogens8040246","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,19]]}}}