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Characterization of intravenous immunoglobulin-mediated functional changes in innate immune cells

2019
Geçkin, Büşranur
Intravenous Immunoglobulin (IVIg) is mainly composed of IgG derived from pooled plasma of healthy individuals and used to treat variety of immune diseases. Low dose administration can activate the immune system in case of immunodeficiencies, while high doses suppress immune responses in autoimmune/autoinflammatory conditions. The mechanisms underlying this disparate effect is poorly understood. Herein, we examined the effects of IVIg treatment on the functionality of specific innate immune cell populations in the absence or presence of various immune activators and investigated whether IVIg can induce trained immunity or not. In this context, we examined the effects of IVIg on neutrophils. Our results showed that high dose of IVIg suppresses PMA-induced NET-formation and TLR7/8 ligandmediated IL-8-production. Conversely, in healthy neutrophils, IVIg stimulated ROSproduction, NET-formation and IL-8-production in response to bacterial and fungal ligands. Similarly, we analysed how IVIg treatment altered responses to TLRmediated immune activation in IVIg co-treated hPBMCs. Results showed that IVIg synergized with most TLR-mediated signalling pathways at lower doses but demonstrated a suppressive effect at the highest dose, especially when coadministered with endosomal TLR agonists. In the second part of the thesis, we explored the possible role of IVIg in inducing trained immunity in monocytes. For this purpose, we trained THP1-Dual cells with IVIg parallel to other reprogramming controls (LPS and PGN). Functional assays based on ROS-production, secondary pro-inflammatory cytokine secretion and NF-κB activation showed that IVIg is a potent inducer of trained immunity, capable of increasing recall responses to bacterial, fungal and/or viral ligands.