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Passively sensitized precision-cut lung slices from marmoset monkeys as a preclinical assay to test novel IgE inhibitors

: Wichmann, Judy; Jiménez Delgado, Sharon Melissa; Curths, Christoph; Becker, Tamara; Eggel, Alexander; Kaup, Franz-Josef; Braun, Armin; Sewald, Katherina; Knauf, Sascha

American Journal of Respiratory and Critical Care Medicine 189 (2014), Art. A1063
ISSN: 1073-449X
ISSN: 0003-0805
ISSN: 1535-4970
American Thoracic Society (ATS International Conference) <2014, San Diego/Calif.>
Fraunhofer ITEM ()

The lack of predictive animal models for human mast cell research contributes to the establishment of translational nonhuman primate models. Due to their close relationship to humans common marmosets (Callithrix jacchus) can be used to investigate mast cell biology in primate airways. Here we hypothesized that due to species homology, linkage of marmoset mast cell receptor and human IgE is possible.
Furthermore we predicted that passively IgE-sensitized marmoset precision-cut lung slices (PCLS) can be used to test the efficacy of a novel disruptive IgE inhibitor.
PCLS were prepared from naïve marmosets (n=10) and human donors (n=3). Isolated lungs or lobes were filled with 1.5% agarose/DMEM. Solidified organs were sliced into 250
Equal to human PCLS, marmoset PCLS incubated in allergic human plasma showed a significant loss of initial airway area after allergen provocation (marmoset: -25.9±4.5%, P<0.001; human: -61.8±18.5%; mean±SEM). As expected, PCLS incubated in non-allergic human plasma did not change airway diameter (marmoset: -5.8±2%; human: -26.0±9.3%; mean±SEM). The maximum of airway constriction was reached within 10 min after allergen challenge. In marmosets, airways re-dilated and reached baseline level (-6.0±3.8%; mean±SEM) which was not the case in human airways that remained contracted until the end of measurement. Supernatants of passively sensitized and allergen challenged marmoset PCLS contained significant higher histamine levels (6.0±0.9ng/mL) compared to non-sensitized slices (1.2±0.6ng/mL; mean±SEM; P<0.001). Treatment of sensitized marmoset PCLS with cetirizine led to histamine release (6.7±2.8ng/mL) but no bronchoconstriction (-6.0±4.8%; mean±SEM; n=2) after HDM application. Treatment of sensitized slices with the disruptive IgE inhibitor prevented HDM-induced airway constriction to a full extent (5.9±3.5%; mean±SEM; n=4).
Based on our results we propose that human IgE binds to marmoset IgE-receptor on mast cells in the lung and that activation leads to bronchoconstriction. Pharmacological intervention demonstrated that marmoset allergen- and mast cell induced bronchoconstriction is IgE and histamine dependent which in contrast to the situation in rodents is similar to human mast cell biology.