Critical role of mammalian target of rapamycin for IL-10 dendritic cell induction by a flagellin A conjugate in preventing allergic sensitization - 04/05/18
, Anna-Helena Fiedler, PhD a, Ann-Christine Junker a, Adam Flaczyk, MSc a, ∗, Sonja Wolfheimer a, Andrea Wangorsch, PhD a, Anke Heinz b, Hendrik Beckert, MSc c, Birgit Nagl d, Barbara Bohle, PhD d, Stefan Vieths, PhD a, Masako Toda, PhD a, Stephan Scheurer, PhD aAbstract |
Background |
Fusion proteins incorporating the Toll-like receptor 5 ligand flagellin are currently undergoing clinical trials as vaccine candidates for many diseases.
Objective |
We studied the mechanisms of immune modulation by a flagellin:allergen fusion protein containing the Toll-like receptor 5 ligand flagellin A from Listeria monocytogenes and the birch pollen allergen Bet v 1 (recombinant flagellin A [rFlaA]:Betv1).
Methods |
BALB/c mice were vaccinated with rFlaA:Betv1 in an experimental Bet v 1 sensitization model. Myeloid dendritic cells (mDCs) were differentiated from mouse bone marrow, and PBMCs were isolated from subjects with birch pollen allergy. Cells were stimulated with equimolar amounts of rFlaA, rBet v 1, rFlaA plus rBet v 1, or the rFlaA:Betv1 conjugate and analyzed for cell activation, cytokine secretion, and metabolic state.
Results |
rFlaA:Betv1 displayed strong immune-modulating properties both in vivo and in vitro, as characterized by secretion of both proinflammatory and anti-inflammatory cytokines from murine mDCs and PBMCs from patients with birch allergy. rFlaA:Betv1 suppressed TH2 responses from Bet v 1–specific CD4+ T cells and prevented allergic sensitization in a mouse allergy model. Aggregation of rFlaA:Betv1 resulted in stronger protein uptake accompanied by an increased resistance to microsomal digestion. Remarkably, rFlaA:Betv1 induced activation of mammalian target of rapamycin, which increased the metabolic activity of the stimulated mDCs. rFlaA:Betv1-mediated IL-10 secretion, but not proinflammatory cytokine secretion, was inhibited by rapamycin in mDCs.
Conclusion |
These results provide evidence that mammalian target of rapamycin is a key player involved in prevention of TH2 responses by flagellin A conjugate vaccines.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Vaccine, Bet v 1, flagellin, rFlaA, fusion protein, birch pollen allergy, IL-10 dendritic cell, mammalian target of rapamycin, metabolism
Abbreviations used : alum, APC, B/A, DC, 2-DO, EGFP, FACS, FITC, FlaA, mDC, mTOR, MyD88, NADH, OVA, PE, PI3K, PRAS40, TLR
Plan
| Part of this work was supported by the German Research Foundation (DFG SCHE 637/3). |
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| Disclosure of potential conflict of interest: S. Schülke has received a grant from the German Research Foundation. A. Flaczyk has received grants from the German Academic Exchange Service and the European Academy of Allergy and Clinical Immunology and has received travel support from the European Academy of Allergy and Clinical Immunology. A. Wangorsch has received a grant from the German Research Foundation. B. Bohle has received grants from the Austrian Science Fund (projects SFB F4610, W1212, and W1248) and the Christian Doppler Research Organization (CD Laboratory for Immunomodulation) and has board memberships with Allergen Online Database, the Paul-Ehrlich-Institut, and the Christian Doppler Research Organization. S. Vieths has received payment for evaluation of a PhD thesis from the Medical University of Vienna; has received payment for evaluation of a Master's thesis from the University of Bonn; has received payment for lectures from Gesellschaft für pädiatrische Allergologie und Umweltmedizin, Ärzteverband Deutscher Allergologen, Swiss Society for Allergy and Immunology, University Hospital Gießen/Marburg, and Pharmacon; has received royalties from Schattauer Allergologie Handbuch Elsevier Nahrungsmittelaller-gien und Intoleranzen, and Karger Food Allergy: Molecular Basis and Clinical Practice; and has received travel support from the German Research Foundation, European Directorate for the Quality of Medicines and Health Care, European Academy of Allergy and Clinical Immunology, World Allergy Organization, Technical University of Munich, Austrian Society for Dermatology and Venerology, AKM Allergiekongress, and International Union of Immunological Societies. S. Scheurer has received a grant from the German Research Foundation. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 141 - N° 5
P. 1786 - mai 2018 Retour au numéro
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