Influence of Mycophenolate on Human Granulocyte and Dendritic Cell Function in the Defense of Aspergillus fumigatus.

J. LOEFFLER, M. MEZGER, C. BLOCKHAUS, W. HEINZ, H. EINSELE;

Author address: 

Medizinische Klinik II, Wuerzburg, Germany.

Abstract: 

Background: There is increasing data that certain immunosuppressive agents not only modulate lymphocyte function, but also interfere with other immune effector cells. Here, we investigated the influence of mycophenolate (MMF) on the immune defence of human dendritic cells (DCs) and polymorphonuclear neutrophils (PMNs), directed against the pathogenic mould A. fumigatus. This mould can cause invasive aspergillosis in immunocompromised patients. Methods: Human monocytes were isolated by magnetic-associated cell sorting followed by differentiation into DCs with GM-CSF and IL-4. Cells were either co-cultivated with MMF (10 µg/ml), with A. fumigatus germ tubes (MOI=1) or with both stimuli. Whole-genome microarray analysis (Affymetrix U133A) or quantitative real-time PCR assays (LightCycler, Roche) were performed to quantify differentially regulated genes. PMNs were obtained from blood using Biocoll separation. Release of reactive oxygen species (ROS) was detected photometrically by using dichlorofluorescein. Results: In DCs, MMF did not affect the gene expression profile and immune response to A. fumigatus. However, if monocytes were treated with MMF at different concentrations, DC development from monocytes was partially blocked resulting in increased apoptosis. In parallel, w observed a subsequent reduced pro-inflammatory cytokine activity (e.g. TNF-α , CXCL10) of DCs in response to A. fumigatus. Quantification of ROS release of PMNs after phagocytosis showed that A. fumigatus germ tubes represent a strong stimulus for the oxidative burst which was further enhanced by MMF (at least 2 fold). Conclusion: MMFmight trigger an acute inflammatory syndrome by enhancing the A. fumigatus induced oxidative burst of PMNs. In addition to inhibitive effects of mycophenolate on lymphocyte proliferation, immune responses might be reduced due to inhibition of DC maturation in the presence of MMF.
2007

abstract No: 

M-1835

Full conference title: 

47th Interscience Conference on Antimicrobial agents and Chemotherapy
    • ICAAC 47th