Abstract

Immunosuppressive drugs are a variety of substances to prevent transplant rejection. There is increasing data that immunosuppressants not only modulate lymphocyte function but also interfere with other immune effector cells. In this study, we analyzed the influence of Mycophenolic acid (MPA) on the activity of human polymorphonuclear neutrophils (PMNs) and dendritic cells (DCs) during the interaction with the mold Aspergillus fumigatus. PMNs were obtained from blood using Bicoll separation. Release of reactive oxygen species (ROS) was detected photometrically by using dichlorofluorescein. Monocytes were isolated by magnetic-associated cell sorting followed by differentiation into DCs using GM-CSF and IL-4. DCs were either co-cultivated with MPA (10 μg/ml), with A. fumigatus germ tubes (MOI=1) or both stimuli. Whole-genome microarray analyses (Affymetrix U133A) or quantitative real-time PCR assays were performed to quantify differentially regulated genes. MPA could be identified as an enhancer of the A. fumigatus induced oxidative burst of PMNs while fungal killing efficiency was not affected. Incubation of fully differentiated Mo-derived DCs in the presence of MPA did not alter gene expression patterns. However, if DCs were treated during early differentiation processes, DC development was influenced by MPA resulting in increased apoptosis. In addition, we revealed impaired expression of a variety of pro-inflammatory immune response genes (TNF-α, CXCL10, IL-12). In conclusion, MPA influences PMN and DC function during immune defense against fungi. MPA triggers an acute inflammatory syndrome by enhancing the A. fumigatus induced oxidative burst. Furthermore, innate and adaptive immune responses might be impaired because of a reduced number of DCs and lower levels of pro-inflammatory cytokines and chemokines.

Author notes

Disclosure:Research Funding: German Research Foundation (DFG), European Union.