title: Escherichia coli heat-labile detoxified enterotoxin modulates dendritic cell function and attenuates allergic airway inflammation.
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.
authors.affiliation: Institute of Microbiology & Immunology, College of Medical, National Cheng-Kung University, Tainan, Taiwan; Development Center for Biotechnology, Taipei, Taiwan.
authors.forename: I-Ping
authors.initials: IP
authors.lastname: Lin
authors.affiliation: Development Center for Biotechnology, Taipei, Taiwan.
authors.forename: Yu-Shen
authors.initials: YS
authors.lastname: Hsu
authors.affiliation: Development Center for Biotechnology, Taipei, Taiwan.
authors.forename: Ssu-Wei
authors.initials: SW
authors.lastname: Kang
authors.affiliation: Institute of Microbiology & Immunology, College of Medical, National Cheng-Kung University, Tainan, Taiwan.
authors.forename: Miao-His
authors.initials: MH
authors.lastname: Hsieh
authors.affiliation: Institute of Microbiology & Immunology, College of Medical, National Cheng-Kung University, Tainan, Taiwan; Department of Pediatrics, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Graduate Institute of Integrated Medicine, School of Chinese Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Jiu-Yao
authors.initials: JY
authors.lastname: Wang
mesh_terms: D000281:Administration, Intranasal; D019264:Adoptive Transfer; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000008:administration & dosage / Q000276:immunology; D001249:Asthma / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D004768:Enterotoxins / Q000276:immunology*; D004926:Escherichia coli / Q000276:immunology*; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007070:Immunoglobulin A / Q000276:immunology; D007071:Immunoglobulin A, Secretory / Q000276:immunology; D051379:Mice; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D018418:Th2 Cells / Q000276:immunology
chemical_list: D000485:Allergens; D039741:Antigens, Dermatophagoides; D016207:Cytokines; D004768:Enterotoxins; D000949:Histocompatibility Antigens Class II; D007070:Immunoglobulin A; D007071:Immunoglobulin A, Secretory