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

Article Article scientifique Article Small-Molecule Immunosuppressive Drugs and Therapeutic Immunoglobulins Differentially Inhibit NK Cell Effector Functions in vitro eng 2019 author Pradier Amandine 660960 author Papaserafeim Maria 758623 author Li Ning 688359 author Rietveld Anke 728253 author Kaestel Charlotte Gotzhe 673922 author Gruaz Lyssia 133767 author Vonarburg Cédric author Spirig Rolf author Puga Yung Gisella 0000-0002-2283-7798 666337 author Seebach Jorg Dieter 647894 556 10.3389/fimmu.2019.00556 30972058 1664-3224 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. IVIg Cyclosporine A and tacrolimus Cytotoxicity and ADCC Everolimus Human NK cells Immunosuppression Methylprednisolone Mycophenolic acid Dewey 616 56 Département de médecine 221 false 518 Cellules NK et récepteurs FcyR dans l'auto-immunité et le rejet de xénotransplantation 856 https://figshare.com/collections/Small-Molecule_Immunosuppressive_Drugs_and_Therapeutic_Immunoglobulins_Differentially_Inhibit_NK_Cell_Effector_Functions_in_vitro/4448900 Frontiers in Immunology 10 c41fefcf-32e7-48a1-88f1-ba7dd6464c9f Article (Published version) Public fimmu-10-00556.pdf 5898182 application/pdf CC BY openAccess Faculté de médecine / Section de médecine clinique / Département de médecine

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Small-Molecule Immunosuppressive Drugs and Therapeutic Immunoglobulins Differentially Inhibit NK Cell Effector Functions in vitro	Frontiers in Immunology			2019	431	203

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Kaestel, Charlotte Gotzhe