title: Immunostimulatory DNA reverses established allergen-induced airway remodeling.
abstract: To determine whether immunostimulatory sequences of DNA (ISS) can reverse established airway remodeling, mice that had developed airway remodeling following 3 mo of repetitive OVA challenges, were treated with ISS for 1-3 mo. Systemic administration of ISS to mice that had already developed established airway remodeling significantly reduced the degree of airway collagen deposition (assessed by lung collagen content, peribronchial trichrome staining, and immunostaining with anticollagen type III and type V Abs). ISS reduced bronchoalveolar lavage and lung levels of TGF-beta1 and reduced the number of TGF-beta1-positive eosinophils and TGF-beta1-positive mononuclear cells recruited to the airway. In vitro studies demonstrated that ISS inhibited TGF-beta1 expression by macrophages (RAW 264.7 cell line and bone marrow-derived macrophages). In addition, ISS significantly reduces lung levels of expression of the chemokine thymus- and activation-regulated chemokine, as well as the number of peribronchial CD4(+) lymphocytes that express Th2 cytokines that promote peribronchial fibrosis. Overall, these studies demonstrate that ISS can reverse features of airway collagen deposition by reducing levels of lung TGF-beta1, as well as by reducing levels of the chemokine thymus- and activation-regulated chemokine and the numbers of peribronchial CD4(+) lymphocytes that drive the ongoing Th2 immune response.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Cho Jae
authors.initials: CJ
authors.lastname: Youn
authors.forename: Marina
authors.initials: M
authors.lastname: Miller
authors.forename: Kwang Je
authors.initials: KJ
authors.lastname: Baek
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Han
authors.forename: Jyothi
authors.initials: J
authors.lastname: Nayar
authors.forename: Sook Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Kirsti
authors.initials: K
authors.lastname: McElwain
authors.forename: Shauna
authors.initials: S
authors.lastname: McElwain
authors.forename: Eyal
authors.initials: E
authors.lastname: Raz
authors.forename: David H
authors.initials: DH
authors.lastname: Broide
mesh_terms: D000199:Actins / Q000032:analysis / Q000096:biosynthesis; D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000485:Allergens / Q000008:administration & dosage*; D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D001483:Base Sequence; D001980:Bronchi / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology; D054414:Chemokine CCL17; D019742:Chemokines, CC / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003094:Collagen / Q000037:antagonists & inhibitors / Q000378:metabolism; D047093:Eosinophil Major Basic Protein / Q000096:biosynthesis; D005260:Female; D005355:Fibrosis; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000378:metabolism; D007958:Leukocyte Count; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009093:Mucus / Q000378:metabolism; D009130:Muscle, Smooth / Q000737:chemistry; D009838:Oligodeoxyribonucleotides / Q000627:therapeutic use*; D010047:Ovalbumin / Q000008:administration & dosage* / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation
chemical_list: D000199:Actins; D000276:Adjuvants, Immunologic; D000485:Allergens; D000943:Antigens, Differentiation; C408982:CPG-oligonucleotide; C499538:Ccl17 protein, mouse; D054414:Chemokine CCL17; D019742:Chemokines, CC; D015850:Interleukin-6; D009838:Oligodeoxyribonucleotides; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C036763:monocyte-macrophage differentiation antigen; D010047:Ovalbumin; D003094:Collagen; D047093:Eosinophil Major Basic Protein