Impact of Immunosuppressive Drugs on Adaptive and Innate Immune Responses to Aspergillus fumigatus Antigens.

Holger Hebart, Andreas Mickan, Ziad Haddad, Juergen Loeffler, Jean-Paul Latge, Hermann Einsele.

Author address: 

Internal Medicine II, Hematology/Oncology, Eberhard-Karls-University, Tuebingen, Germany; Laboratoire des Aspergillus, Institute Pasteur, Paris, France

Abstract: 

Appropriate activation of the innate and adaptive immune system is crucial for the successful control of invasive aspergillosis (IA). Acute and chronic graft-versus-host disease as well as corticosteroids were described as major risk factors for the development of IA. In this study, we assessed the impact of immunosuppressive agents (dexamethasone, rapamycin, Cyclosporin A, FK506) on the A. fumigatus induced activation of monocyte-derived immature dendritic cells (iDC) and A. fumigatus-specific T-cell responses in well established cell culture models. Immature DCs were found to be activated and to differentiate into mature DCs in response to A. fumigatus antigens. The upregulation of CD86 was inhibited by dexamethasone (D) in 3 out of 3 experiments, and of CD40 and CD80 in 2/3. CSA and FK506 had a variable impact on the upregulation of CD86, but not on CD40 and CD80, whereas the expression of co-stimulatory molecules was found unchanged upon incubation with rapamycin. Autologous DCs were found to restore A. fumigatus-specific T-cell responses. T-cell proliferation to A. fumigatus hyphae and a cellular extract of the culture filtrate were found to be strongly inhibited by rapamycin and dexamethasone (n=3), whereas the effect of CSA and FK506 (n=3) at the concentrations analysed was variable. The release of IFN-g in culture supernatants upon stimulation with A. fumigatus antigens was strongly reduced in the presence of rapamycin (n=3), whereas the release of IL-4 was found to be increased in the majority of experiments (n=3). Comparable results were observed upon stimulation with tetanus toxoid and a CMV lysate (n=3). These data indicate, that A. fumigatus-spec. T-cell responses may be directed towards a TH2 phenotype in the presence of immunosuppressive agents. In summary, immunosuppressive agents were found to exert differential effects on adaptive and innate immune responses directed against A. fumigatus. Whereas dexamethasone was found to modulate the expression of co-stimulatory molecules on A. fumigatus activated iDCs and to suppress A. fumigatus-specific lymphoproliferation, rapamycin exerted only minor effects on DC-activation but had a strong impact on A. fumigatus-induced T-cell responses. These results may help to tailor immunosuppressive regimens in patients at high risk for invasive aspergillosis.
2004

abstract No: 

2222

Full conference title: 

46th American Society for Haematology
    • ASH 46th (2004)