Immunostimulatory DNA reverses established allergen-induced airway remodeling.
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.
Youn
Cho Jae
CJ
Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Miller
Marina
M
Baek
Kwang Je
KJ
Han
Ji Won
JW
Nayar
Jyothi
J
Lee
Sook Young
SY
McElwain
Kirsti
K
McElwain
Shauna
S
Raz
Eyal
E
Broide
David H
DH
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
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