title: Vaccination with heat-killed Listeria as adjuvant reverses established allergen-induced airway hyperreactivity and inflammation: role of CD8+ T cells and IL-18.
abstract: Asthma is a respiratory disorder characterized by airway hyperreactivity (AHR) and inflammation and is associated with high serum IgE and overproduction of IL-4, IL-5, and IL-13 by allergen-specific Th2 cells. Our previous studies demonstrated that heat-killed Listeria monocytogenes (HKL) as an adjuvant in immunotherapy successfully reversed ongoing Ag-specific Th2-dominated responses toward Th1-dominated responses, but it was unclear if such immune modulation could reverse ongoing, established disease in target organs such as the lung. In this paper we show that a single dose of Ag plus HKL as adjuvant significantly reduced AHR in a murine model for asthma and reversed established AHR when given late after allergen sensitization. HKL as adjuvant also dramatically inhibited airway inflammation, eosinophilia, and mucus production, significantly reduced Ag-specific IgE and IL-4 production, and dramatically increased Ag-specific IFN-gamma synthesis. The inhibitory effect of HKL on AHR depended on the presence of IL-12 and CD8+ T cells and was associated with an increase of IL-18 mRNA expression. Thus, our results demonstrate that HKL as an adjuvant for immunotherapy mediates immune deviation from a pathological Th2-dominated response toward a protective immune response in peripheral lymphoid tissues and in the lungs and may be clinically effective in the treatment of patients with established asthma and allergic disease.
authors.affiliation: Division of Immunology and Transplantation Biology, Department of Pediatrics, Stanford University, CA 94305, USA.
authors.forename: G
authors.initials: G
authors.lastname: Hansen
authors.forename: V P
authors.initials: VP
authors.lastname: Yeung
authors.forename: G
authors.initials: G
authors.lastname: Berry
authors.forename: D T
authors.initials: DT
authors.lastname: Umetsu
authors.forename: R H
authors.initials: RH
authors.lastname: DeKruyff
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000281:Administration, Intranasal; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology / Q000627:therapeutic use; D001428:Bacterial Vaccines / Q000276:immunology*; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D006358:Hot Temperature; D007166:Immunosuppressive Agents / Q000276:immunology / Q000627:therapeutic use; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D007271:Injections, Intradermal; D020382:Interleukin-18 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008088:Listeriosis / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D008168:Lung / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000378:metabolism; D015164:Vaccines, Inactivated / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000485:Allergens; D000942:Antigens, Bacterial; D001428:Bacterial Vaccines; D016207:Cytokines; D007166:Immunosuppressive Agents; D020382:Interleukin-18; D012333:RNA, Messenger; D015164:Vaccines, Inactivated; D010047:Ovalbumin