title: Uricase Inhibits Nitrogen Dioxide-Promoted Allergic Sensitization to Inhaled Ovalbumin Independent of Uric Acid Catabolism.
abstract: Nitrogen dioxide (NO2) is an environmental air pollutant and endogenously generated oxidant that contributes to the exacerbation of respiratory disease and can function as an adjuvant to allergically sensitize to an innocuous inhaled Ag. Because uric acid has been implicated as a mediator of adjuvant activity, we sought to determine whether uric acid was elevated and participated in a mouse model of NO2-promoted allergic sensitization. We found that uric acid was increased in the airways of mice exposed to NO2 and that administration of uricase inhibited the development of OVA-driven allergic airway disease subsequent to OVA challenge, as well as the generation of OVA-specific Abs. However, uricase was itself immunogenic, inducing a uricase-specific adaptive immune response that occurred even when the enzymatic activity of uricase had been inactivated. Inhibition of the OVA-specific response was not due to the capacity of uricase to inhibit the early steps of OVA uptake or processing and presentation by dendritic cells, but occurred at a later step that blocked OVA-specific CD4(+) T cell proliferation and cytokine production. Although blocking uric acid formation by allopurinol did not affect outcomes, administration of ultra-clean human serum albumin at protein concentrations equivalent to that of uricase inhibited NO2-promoted allergic airway disease. These results indicate that, although uric acid levels are elevated in the airways of NO2-exposed mice, the powerful inhibitory effect of uricase administration on allergic sensitization is mediated more through Ag-specific immune deviation than via suppression of allergic sensitization, a mechanism to be considered in the interpretation of results from other experimental systems.
authors.affiliation: Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, University of Vermont, Burlington, VT 05405;
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Ather
authors.affiliation: Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, University of Vermont, Burlington, VT 05405; Cellular, Molecular, and Biomedical Sciences Graduate Program, University of Vermont, Burlington, VT 05405;
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Burgess
authors.affiliation: Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, University of Vermont, Burlington, VT 05405;
authors.forename: Laura R
authors.initials: LR
authors.lastname: Hoyt
authors.affiliation: Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, University of Vermont, Burlington, VT 05405;
authors.forename: Matthew J
authors.identifier: 0000-0003-3840-8952
authors.initials: MJ
authors.lastname: Randall
authors.affiliation: Department of Chemistry, University of Vermont, Burlington, VT 05405; and.
authors.forename: Mridul K
authors.initials: MK
authors.lastname: Mandal
authors.affiliation: Cellular, Molecular, and Biomedical Sciences Graduate Program, University of Vermont, Burlington, VT 05405; Department of Chemistry, University of Vermont, Burlington, VT 05405; and.
authors.forename: Dwight E
authors.identifier: 0000-0003-2715-6104
authors.initials: DE
authors.lastname: Matthews
authors.affiliation: Cellular, Molecular, and Biomedical Sciences Graduate Program, University of Vermont, Burlington, VT 05405; Department of Surgery, University of Vermont, Burlington, VT 05405.
authors.forename: Jonathan E
authors.identifier: 0000-0003-2673-9148
authors.initials: JE
authors.lastname: Boyson
authors.affiliation: Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, University of Vermont, Burlington, VT 05405; Cellular, Molecular, and Biomedical Sciences Graduate Program, University of Vermont, Burlington, VT 05405; matthew.poynter@uvm.edu.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Poynter
mesh_terms: D056704:Adaptive Immunity; D000485:Allergens / Q000008:administration & dosage; D000493:Allopurinol / Q000008:administration & dosage; D000818:Animals; D017951:Antigen Presentation; D001249:Asthma / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology*; D008168:Lung / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009585:Nitrogen Dioxide / Q000633:toxicity*; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology*; D012709:Serum Albumin / Q000008:administration & dosage; D018418:Th2 Cells; D014503:Urate Oxidase / Q000008:administration & dosage* / Q000378:metabolism; D014527:Uric Acid / Q000378:metabolism*
chemical_list: D000485:Allergens; D016207:Cytokines; D012709:Serum Albumin; D014527:Uric Acid; D000493:Allopurinol; D010047:Ovalbumin; D014503:Urate Oxidase; D009585:Nitrogen Dioxide