Distinct Effects of Immunosuppressive Drugs on the Anti-Aspergillus Activity of Human Natural Killer Cells.

Schmidt Schmidt,Lehrnbecher Lehrnbecher,Schubert Schubert,Demir Demir

doi:10.3390/pathogens8040246

Schmidt Schmidt, Lehrnbecher Lehrnbecher + Show 2 more

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https://doi.org/10.3390/pathogens8040246

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Abstract

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-γ, 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.

Highlights

Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are at an increased risk for invasive fungal disease (IFD), with Aspergillus fumigatus as the fungal pathogen most commonly isolated [1]
Anti-Aspergillus Activity of Human Natural Killer (NK) Cells Co-Incubated with Immunosuppressive Agents
When coco-incubating fumigatus hyphae with both human cells and immunosuppressive drugs, incubating A. fumigatus hyphae with both human NK cells and immunosuppressive drugs, the the measured hyphal damage represents the net-effect of the damage hyphal mediated damage mediated by measured hyphal damage represents the net-effect of the hyphal by NK cells

Summary

Introduction

Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are at an increased risk for invasive fungal disease (IFD), with Aspergillus fumigatus as the fungal pathogen most commonly isolated [1]. Despite new and potent antifungal agents, morbidity and mortality of invasive aspergillosis in HSCT recipients is unacceptably high, which explains the growing interest in immunotherapeutic approaches, such as adoptively transferring antifungal effector cells or administering of cytokines or interferons in this setting [2,3]. NK cells are able to exert direct antifungal activity via cytotoxic molecules, such as perforin, and modulate the antifungal host response via the release of molecules, Pathogens 2019, 8, 246; doi:10.3390/pathogens8040246 www.mdpi.com/journal/pathogens. Pathogens 2019, 8, x FOR PEER REVIEW suchrelease as interferon (IFN)-γ,such granulocyte-macrophage colony-stimulating factor (GM-CSF). RANTES the of molecules, as interferon (IFN)-γ, granulocyte-macrophage colony-stimulating T-cell expressed, and secreted; chemokine ligand 5). Secreted; contrast, theligand impact activating and inhibitory.

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