Small-Molecule Immunosuppressive Drugs and Therapeutic Immunoglobulins Differentially Inhibit NK Cell Effector Functions in vitro

Autor: Anke Rietveld, Amandine Pradier, Rolf Spirig, Lyssia Gruaz, Gisella Puga Yung, Charlotte Gotzhe Kaestel, Cédric Vonarburg, Maria Papaserafeim, Ning Li, Jorg Dieter Seebach
Rok vydání: 2019
Předmět:
lcsh:Immunologic diseases. Allergy
IVIg
0301 basic medicine
T-Lymphocytes
Immunology
Immunoglobulins
human NK cells
Pharmacology
Methylprednisolone
Interferon-gamma
03 medical and health sciences
Cyclosporine A and tacrolimus
0302 clinical medicine
Immune system
hemic and lymphatic diseases
medicine
Humans
Immunology and Allergy
Interferon gamma
Everolimus
Mycophenolic acid
IL-2 receptor
Cytotoxicity
Cells
Cultured
Cell Proliferation
Original Research
ddc:616
Antibody-dependent cell-mediated cytotoxicity
immunosuppression
Human NK cells
Chemistry
Cytotoxicity and ADCC
cytotoxicity and ADCC
Degranulation
everolimus
NKG2D
methylprednisolone
Killer Cells
Natural
030104 developmental biology
Interleukin 12
lcsh:RC581-607
Immunosuppression
Immunosuppressive Agents
mycophenolic acid
cyclosporine A and tacrolimus
030215 immunology
medicine.drug
Zdroj: Frontiers in Immunology
Frontiers in Immunology, Vol. 10 (2019) P. 556
Frontiers in Immunology, Vol 10 (2019)
ISSN: 1664-3224
DOI: 10.3389/fimmu.2019.00556
Popis: Small-molecule immunosuppressive drugs (ISD) prevent graft rejection mainly by inhibiting T lymphocytes. Therapeutic immunoglobulins (IVIg) are used for substitution, antibody-mediated rejection (AbMR) and HLA-sensitized recipients by targeting distinct cell types. Since the effect of ISD and IVIg on natural killer (NK) cells remains somewhat controversial in the current literature, the aim of this comparative study was to investigate healthy donor's human NK cell functions after exposure to ISD and IVIg, and to comprehensively review the current literature. NK cells were incubated overnight with IL2/IL12 and different doses and combinations of ISD and IVIg. Proliferation was evaluated by 3[H]-thymidine incorporation; phenotype, degranulation and interferon gamma (IFNγ) production by flow cytometry and ELISA; direct NK cytotoxicity by standard 51[Cr]-release and non-radioactive DELFIA assays using K562 as stimulator and target cells; porcine endothelial cells coated with human anti-pig antibodies were used as targets in antibody-dependent cellular cytotoxicity (ADCC) assays. We found that CD69, CD25, CD54, and NKG2D were downregulated by ISD. Proliferation was inhibited by methylprednisolone (MePRD), mycophenolic acid (MPA), and everolimus (EVE). MePRD and MPA reduced degranulation, MPA only of CD56bright NK cells. MePRD and IVIg inhibited direct cytotoxicity and ADCC. Combinations of ISD demonstrated cumulative inhibitory effects. IFNγ production was inhibited by MePRD and ISD combinations, but not by IVIg. In conclusion, IVIg, ISD and combinations thereof differentially inhibit NK cell functions. The most potent drug with an effect on all NK functions was MePRD. The fact that MePRD and IVIg significantly block NK cytotoxicity, especially ADCC, has major implications for AbMR as well as therapeutic strategies targeting cancer and immune cells with monoclonal antibodies.
Databáze: OpenAIRE
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