title: Natural innate cytokine response to immunomodulators and adjuvants in human precision-cut lung slices.
abstract: Prediction of lung innate immune responses is critical for developing new drugs. Well-established immune modulators like lipopolysaccharides (LPS) can elicit a wide range of immunological effects. They are involved in acute lung diseases such as infections or chronic airway diseases such as COPD. LPS has a strong adjuvant activity, but its pyrogenicity has precluded therapeutic use. The bacterial lipopeptide MALP-2 and its synthetic derivative BPPcysMPEG are better tolerated. We have compared the effects of LPS and BPPcysMPEG on the innate immune response in human precision-cut lung slices. Cytokine responses were quantified by ELISA, Luminex, and Meso Scale Discovery technology. The initial response to LPS and BPPcysMPEG was marked by coordinated and significant release of the mediators IL-1β, MIP-1β, and IL-10 in viable PCLS. Stimulation of lung tissue with BPPcysMPEG, however, induced a differential response. While LPS upregulated IFN-γ, BPPcysMPEG did not. This traces back to their signaling pathways via TLR4 and TLR2/6. The calculated exposure doses selected for LPS covered ranges occurring in clinical studies with human beings. Correlation of obtained data with data from human BAL fluid after segmental provocation with endotoxin showed highly comparable effects, resulting in a coefficient of correlation >0.9. Furthermore, we were interested in modulating the response to LPS. Using dexamethasone as an immunosuppressive drug for anti-inflammatory therapy, we found a significant reduction of GM-CSF, IL-1β, and IFN-γ. The PCLS-model offers the unique opportunity to test the efficacy and toxicity of biological agents intended for use by inhalation in a complex setting in humans.
authors.affiliation: Fraunhofer Institute for Toxicology and Experimental Medicine, Division of Immunology, Allergy and Airway Research, Nikolai-Fuchs-Str. 1, D-30625 Hannover, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Switalla
authors.affiliation: Fraunhofer Institute for Toxicology and Experimental Medicine, Division of Immunology, Allergy and Airway Research, Nikolai-Fuchs-Str. 1, D-30625 Hannover, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Lauenstein
authors.affiliation: Fraunhofer Institute for Toxicology and Experimental Medicine, Division of Immunology, Allergy and Airway Research, Nikolai-Fuchs-Str. 1, D-30625 Hannover, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Prenzler
authors.affiliation: Fraunhofer Institute for Toxicology and Experimental Medicine, Division of Immunology, Allergy and Airway Research, Nikolai-Fuchs-Str. 1, D-30625 Hannover, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Knothe
authors.affiliation: Klinikum Region Hannover (KRH), Hannover, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Förster
authors.affiliation: Klinikum Region Hannover (KRH), Hannover, Germany.
authors.forename: H-G
authors.initials: HG
authors.lastname: Fieguth
authors.affiliation: Klinikum Region Hannover (KRH), Hannover, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Pfennig
authors.affiliation: Fraunhofer Institute for Toxicology and Experimental Medicine, Division of Immunology, Allergy and Airway Research, Nikolai-Fuchs-Str. 1, D-30625 Hannover, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Schaumann
authors.affiliation: Institute of Pharmacology and Toxicology, RWTH Aachen, Wendlingweg 2, 52074 Aachen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Martin
authors.affiliation: Helmholtz Centre for Infection Research, Department of Vaccinology and Applied Microbiology, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
authors.forename: C A
authors.initials: CA
authors.lastname: Guzman
authors.affiliation: Helmholtz Centre for Infection Research, Department of Vaccinology and Applied Microbiology, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Ebensen
authors.affiliation: Fraunhofer Institute for Toxicology and Experimental Medicine, Division of Immunology, Allergy and Airway Research, Nikolai-Fuchs-Str. 1, D-30625 Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Müller
authors.affiliation: Fraunhofer Institute for Toxicology and Experimental Medicine, Division of Immunology, Allergy and Airway Research, Nikolai-Fuchs-Str. 1, D-30625 Hannover, Germany.
authors.forename: J M
authors.initials: JM
authors.lastname: Hohlfeld
authors.affiliation: Fraunhofer Institute for Toxicology and Experimental Medicine, Division of Immunology, Allergy and Airway Research, Nikolai-Fuchs-Str. 1, D-30625 Hannover, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Krug
authors.affiliation: Fraunhofer Institute for Toxicology and Experimental Medicine, Division of Immunology, Allergy and Airway Research, Nikolai-Fuchs-Str. 1, D-30625 Hannover, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Braun
authors.affiliation: Fraunhofer Institute for Toxicology and Experimental Medicine, Division of Immunology, Allergy and Airway Research, Nikolai-Fuchs-Str. 1, D-30625 Hannover, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Sewald
mesh_terms: D000328:Adult; D000893:Anti-Inflammatory Agents / Q000276:immunology; D054407:Chemokine CCL4 / Q000276:immunology; D016207:Cytokines / Q000276:immunology*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007155:Immunologic Factors / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology; D055666:Lipopeptides / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008168:Lung / Q000276:immunology*; D008297:Male; D011092:Polyethylene Glycols; D051193:Toll-Like Receptors / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D054407:Chemokine CCL4; D016207:Cytokines; C508609:IL10 protein, human; D007155:Immunologic Factors; D053583:Interleukin-1beta; D055666:Lipopeptides; D008070:Lipopolysaccharides; C549816:S-(2,3-bispalmitoyloxypropyl)-cysteinyl-amido-monomethoxyl polyethylene glycol; D051193:Toll-Like Receptors; D016753:Interleukin-10; D011092:Polyethylene Glycols; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor