title: Intranasal IL-12 produces discreet pulmonary and systemic effects on allergic inflammation and airway reactivity.
abstract: IL-12 modulates T cell responses between helper T cells Th2 and Th1; however, the therapeutic potential of IL-12 for allergic diseases either directly or as an adjuvant in allergen therapy has been controversial. The role of intranasal IL-12 as an adjuvant in modulating the grass pollen allergen (GAL) therapy-induced systemic immune response and lung-specific inflammation and airway reactivity was examined in this study using a mouse model of established allergic asthma. The effects of intranasal or nebulized IL-12 with or without intranasal anti-IFN-gamma antibody were examined in groups of control and allergen-sensitized or -challenged mice. T cell cytokine patterns, antibody response profiles, pulmonary inflammation and airway reactivity were examined. Intranasal IL-12 was found to be more effective in the Th2-Th1 shifting of immune response and anti-inflammatory activity in the lung compared to nebulized IL-12 at the given doses. Intranasal IL-12 significantly decreased production of IFN-gamma, eotaxin and LTC4/D4/E4 in the lung and decreased eosinophil infiltration, resulting in attenuated airway hyper-responsiveness in GAL-sensitized (GS) mice. In contrast, intranasal IL-12 significantly increased IFN-gamma production in the thoracic lymph node cultures and decreased the IL-5/IFN-gamma ratio, suggesting a Th2-Th1 shift. Also, intranasal IL-12 increased GAL-specific IgG2a antibody response, while the IgE response remained unaffected. The systemic effects of IL-12 were IFN-gamma dependent. IL-12 induces differential expression of its own receptor beta1 and beta2 subunits in the lung tissues to augment IL-12 responsiveness. Together, these results demonstrate that intranasal IL-12 is effective in shifting the systemic immune response in the direction of Th1 in IFN-gamma-dependent manner, while decreasing pulmonary inflammation and airway reactivity independent of IFN-gamma. Thus, intranasal delivery of IL-12 may provide an approach for the treatment of asthma and may be useful as an adjuvant in local nasal immunotherapy (IT) and in asthma.
authors.affiliation: Department of Internal Medicine, Joy McCann Culverhouse Airway Disease Research Center, Tampa, FL 33612, USA.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Matsuse
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Kong
authors.forename: Jianan
authors.initials: J
authors.lastname: Hu
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Wolf
authors.forename: Richard F
authors.initials: RF
authors.lastname: Lockey
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Mohapatra
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000280:Administration, Inhalation; D000281:Administration, Intranasal; D000403:Airway Resistance / Q000187:drug effects / Q000276:immunology; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects* / Q000276:immunology; D001249:Asthma / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D007074:Immunoglobulin G / Q000276:immunology; D007249:Inflammation; D007371:Interferon-gamma / Q000032:analysis / Q000276:immunology; D018664:Interleukin-12 / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008811:Mice, Inbred DBA; D009330:Nebulizers and Vaporizers; D011058:Pollen / Q000276:immunology; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000276:immunology; D053707:Receptors, Interleukin-12; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000485:Allergens; C508440:Il12rb1 protein, mouse; C508443:Il12rb2 protein, mouse; D007074:Immunoglobulin G; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018664:Interleukin-12; D007371:Interferon-gamma