title: Interleukin-10 gene transfer to the airway regulates allergic mucosal sensitization in mice.
abstract: The objective of this study was to investigate the effect of airway gene transfer of interleukin (IL)-10, a cytokine with potent anti-inflammatory and immunoregulatory activities, on allergic mucosal sensitization. We used a recently described murine model that involves repeated exposures to aerosolized ovalbumin (OVA), daily for 10 d, in the context of granulocyte macrophage colony-stimulating factor (GM-CSF) expression in the airway environment achieved by intranasal delivery of a replication-deficient adenovirus carrying the GM-CSF transgene. The resulting inflammatory response was characterized by a T-helper 2 cytokine profile and marked airway eosinophilia. After complete resolution of the inflammatory response (Day 28), a single exposure to OVA reconstituted airway eosinophilia and induced airway hyperresponsiveness. We show that concurrent expression of IL-10 inhibited GM-CSF-driven OVA-specific inflammation in a dose-dependent manner. Specifically, IL-10 decreased the number of mononuclear cells, neutrophils, and eosinophils in the bronchoalveolar lavage fluid (BALF). Histologic evaluation of the tissue corroborated the findings in the BALF. Concurrent expression of IL-10 at the time of mucosal sensitization abrogated both the cellular and physiologic recall responses in vivo. Studies in interferon (IFN)-gamma knockout mice demonstrated that prevention of airway eosinophilia by IL-10 was IFN-gamma-independent and that expression of IL-10 was associated with decreased levels of IL-4, IL-5, and tumor necrosis factor-alpha in the BALF. Flow cytometric analysis of dispersed lung cells showed that expression of IL-10 in the airway reduced the absolute number of Class II major histocompatibility complex (MHC)(+)/CD11c(+) (dendritic cells) and Class II MHC(+)/Mac-1(bright) (macrophages) cells expressing the costimulatory molecules B7.1 and B7.2 by 30%. However, IL-10 coexpression did not prevent expansion of CD4 and CD8 T cells or expression of the early activation marker CD69 on T cells. Thus, airway gene transfer of IL-10 altered the immune response to OVA in a way that resulted in inhibition of airway inflammation. These findings suggest that development of an immunoregulatory strategy based on IL-10, alone or in combination with GM-CSF, warrants further consideration.
authors.affiliation: Department of Pathology and Molecular Medicine, Immunology and Infection Programme, Center for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: M R
authors.initials: MR
authors.lastname: Stämpfli
authors.forename: M
authors.initials: M
authors.lastname: Cwiartka
authors.forename: B U
authors.initials: BU
authors.lastname: Gajewska
authors.forename: D
authors.initials: D
authors.lastname: Alvarez
authors.forename: S A
authors.initials: SA
authors.lastname: Ritz
authors.forename: M D
authors.initials: MD
authors.lastname: Inman
authors.forename: Z
authors.initials: Z
authors.lastname: Xing
authors.forename: M
authors.initials: M
authors.lastname: Jordana
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism; D000954:Antigens, Surface / Q000096:biosynthesis; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004802:Eosinophilia / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology; D005260:Female; D018014:Gene Transfer Techniques; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D007073:Immunoglobulin E / Q000097:blood; D007371:Interferon-gamma / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000276:immunology; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D016753:Interleukin-10; D007073:Immunoglobulin E; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D010047:Ovalbumin