Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 137, Issue 2, Pages 426-435Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2015.07.010
Keywords
Asthma; Toll-like receptor 5; flagellin; dendritic cells; regulatory T cells
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Funding
- Korean Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) - Ministry of Health and Welfare, Republic of Korea [HI14C0187]
- [IBS-R005-G1-2015-a00]
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Background: Although the hygiene hypothesis suggests that microbial infections could subvert asthma and thus a microbial product might serve as a therapeutic adjuvant for asthma, the relationship between bacterial components and asthma is complex. Recently, low levels of flagellin, the Toll-like receptor (TLR) 5 ligand, have been reported to promote asthma. Objective: We show that a therapeutic dose of flagellin suppresses asthma and that the effect occurs through generating regulatory dendritic cells (rDCs) and regulatory T (Treg) cells. Methods: Ovalbumin (OVA)-induced wild-type and TLR5 knockout asthmatic mice were treated intranasally with a mixture of OVA and 10 mu g of a flagellin B (FlaB; of Vibrio vulnificus). OVA/FlaB-treated rDCs were adoptively transferred to mice with OVA-induced asthma. Anti-CD25 mAb was used to deplete Treg cells. A mixture of house dust mite (HDM) and FlaB was used to treat mice with HDM-induced asthma. Blood CD14(+) monocyte-derived dendritic cells from HDM-sensitive asthmatic patients were treated with FlaB and incubated with autologous CD14(+) T cells. Results: An OVA/FlaB mixture ameliorated OVA-induced asthma by inhibiting T(H)1/T(H)2/T(H)17 responses in a TLR5-dependent manner through generating rDCs and Treg cells. The adoptive transfer of OVA/FlaB-treated dendritic cells inhibited OVA-induced asthma, whereas the depletion of CD25(+) cells eliminated the inhibitory effect. A similar effect of FlaB was observed in mice with HDM-induced asthma. In patients with HDM-sensitive asthma, FlaB-treated rDCs inhibited HDM-stimulated T(H)1/T(H)2 responses while enhancing Treg cells in an IL-10-dependent manner. Conclusion: These findings collectively suggest that flagellin could be used as a tolerogenic adjuvant to treat allergic asthma.
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