title: Prevention of Th2-like cell responses by coadministration of IL-12 and IL-18 is associated with inhibition of antigen-induced airway hyperresponsiveness, eosinophilia, and serum IgE levels.
abstract: Allergic asthma is thought to be regulated by Th2 cells, and inhibiting this response is a promising mode of intervention. Many studies have focused on differentiation of Th cells to the Th1 or Th2 subset in vitro. IL-4 is essential for Th2 development, while IL-12 induces Th1 development, which can be enhanced by IL-18. In the present study, we investigated whether IL-12 and IL-18 were able to interfere in Th2 development and the associated airway symptoms in a mouse model of allergic asthma. Mice were sensitized with OVA using a protocol that induces IgE production. Repeated challenges by OVA inhalation induced elevated serum levels of IgE, airway hyperresponsiveness, and a predominantly eosinophilic infiltrate in the bronchoalveolar lavage concomitant with the appearance of Ag-specific Th2-like cells in lung tissue and lung-draining lymph nodes. Whereas treatments with neither IL-12 nor IL-18 during the challenge period were effective, combined treatment of IL-12 and IL-18 inhibited Ag-specific Th2-like cell development. This inhibition was associated with an absence of IgE up-regulation, airway hyperresponsiveness, and cellular infiltration in the lavage. These data show that, in vivo, the synergistic action of IL-12 and IL-18 is necessary to prevent Th2-like cell differentiation, and consequently inhibits the development of airway symptoms in a mouse model of allergic asthma.
authors.affiliation: Department of Pharmacology and Pathophysiology, Utrecht University, The Netherlands. C.L.Hofstra@Pharm.UU.NL
authors.forename: C L
authors.initials: CL
authors.lastname: Hofstra
authors.forename: I
authors.initials: I
authors.lastname: Van Ark
authors.forename: G
authors.initials: G
authors.lastname: Hofman
authors.forename: M
authors.initials: M
authors.lastname: Kool
authors.forename: F P
authors.initials: FP
authors.lastname: Nijkamp
authors.forename: A J
authors.initials: AJ
authors.lastname: Van Oosterhout
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology / Q000628:therapy*; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004357:Drug Synergism; D004802:Eosinophilia / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D007073:Immunoglobulin E / Q000097:blood*; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D018664:Interleukin-12 / Q000494:pharmacology / Q000627:therapeutic use*; D020382:Interleukin-18 / Q000494:pharmacology / Q000627:therapeutic use*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology / Q000633:toxicity; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013047:Specific Pathogen-Free Organisms; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology
chemical_list: D016207:Cytokines; D007155:Immunologic Factors; D020382:Interleukin-18; D011994:Recombinant Proteins; D018664:Interleukin-12; D007073:Immunoglobulin E; D010047:Ovalbumin