Abstract
Various mutant forms of Escherichia coli heat-labile enterotoxin (LT) have been used as a mucosal adjuvant for vaccines, as it enhances immune responses to specific antigens including antigen-specific IgA antibodies when administrated intranasally or orally. We hypothesized that a detoxified mutant form of LT, LTS61K, could modulate dendritic cell (DC) function and alleviate allergen-induced airway inflammation. Two protocols, preventative and therapeutic, were used to evaluate the effects of LTS61K in a Dermatophagoides pteronyssinus (Der p)-sensitized and challenged murine model of asthma. LTS61K or Der p-primed bone marrow-derived dendritic cells (BMDCs) were also adoptively transferred into Der p-sensitized and challenged mice. Intranasal inoculations with LTS61K or LTS61K/Der p decreased allergen-induced airway inflammation and alleviated systemic TH2-type immune responses. Bronchoalveolar lavage fluid (BALF) and sera from LTS61K/Der p-treated mice also had higher concentrations of Der p-specific immunoglobulin (Ig) A than those of other groups. In vitro, BMDCs stimulated with Der p underwent cellular maturation and secreted proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)α In contrast, Der p-stimulated BMDCs that were pretreated with LTS61K showed decreased IL-6 and TNFα production and were less mature. Intratracheal adoptive transfer of LTS61K- or LTS61K/Der p-primed BMDCs into Der p-sensitized mice reduced inflammatory cell infiltration and TH2-type chemokines in BALF and alleviated airway inflammation in treated mice. LTS61K influenced DC maturation and decreased inflammatory cytokine production. Moreover, LTS61K/Der p induced increased Der p-specific IgA production to decrease allergic TH2 cytokine responses and alleviated airway inflammation in Der p-sensitized mice. These results suggest that the immunomodulatory effects of LTS61K may have clinical applications for allergy and asthma treatment.
Highlights
Allergic asthma is a chronic airway inflammatory disease that is characterized by eosinophil infiltration, bronchial epithelium damage, and airway hyper-reactivity (AHR), which result from immunopathogenic TH2-type responses to environmental allergens, such as house dust mites (HDMs) [1]
Our results showed that mice that were i.n. treated with LTS61K combined with Dermatophagoides pteronyssinus (Der p) had increased Der p-specific IgA levels either locally (BALF) or in the systemic circulation
We cannot exclude an indirect stimulatory effect of LTS61K due to its possible interactions with other cell types such as macrophages or bronchial epithelial cells, we believe that LTS61K promulgated these effects by altering dendritic cell (DC) function and maturation, thereby programming DCs to induce IgA-producing B cells and regulatory T cells
Summary
Allergic asthma is a chronic airway inflammatory disease that is characterized by eosinophil infiltration, bronchial epithelium damage, and airway hyper-reactivity (AHR), which result from immunopathogenic TH2-type responses to environmental allergens, such as house dust mites (HDMs) [1]. An ultimate adaptive T-cell immune response may be determined by the differentiation and maturation status, expression profile of costimulatory molecules, and specific pattern-recognition receptors that are used for the recognition of antigens by DCs [6]. This role of DCs for determining a particular immune response may provide a target for alleviating or possibly modulating airway inflammation in allergic asthma patients
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