Immunostimulatory DNA sequences inhibit IL-5, eosinophilic inflammation, and airway hyperresponsiveness in mice.
We have used a mouse model of allergen-induced airway hyperresponsiveness to demonstrate that immunostimulatory DNA sequences (ISS) containing a CpG DNA motif significantly inhibit airway eosinophilia and reduce responsiveness to inhaled methacholine. ISS not only inhibited eosinophilia of the airway (by 93%) and lung parenchyma (91%), but also significantly inhibited blood eosinophilia (86%), suggesting that ISS was exerting a significant effect on the bone marrow production of eosinophils. The inhibition of the bone marrow production of eosinophils by 58% was associated with a significant inhibition of T cell-derived cytokine generation (IL-5, granulocyte-macrophage CSF, and IL-3). ISS exerted this inhibitory effect on T cell cytokine production indirectly by stimulating monocytes/macrophages and NK cells to generate IL-12 and IFNs. The onset of the ISS effect on reducing the number of tissue eosinophils was both immediate (within 1 day of administration) and sustained (lasted 6 days), and was not due to ISS directly inducing eosinophil apoptosis. ISS was effective in inhibiting eosinophilic airway inflammation when administered either systemically (i.p.), or mucosally (i.e., intranasally or intratracheally). Interestingly, a single dose of ISS inhibited airway eosinophilia as effectively as daily injections of corticosteroids for 7 days. Moreover, while both ISS and corticosteroids inhibited IL-5 generation, only ISS was able to induce allergen-specific IFN-gamma production and redirect the immune system toward a Th1 response. Thus, systemic or mucosal administration of ISS before allergen exposure could provide a novel form of active immunotherapy in allergic diseases.
Broide
D
D
Department of Medicine, University of California at San Diego, La Jolla 92093-0635, USA.
Schwarze
J
J
Tighe
H
H
Gifford
T
T
Nguyen
M D
MD
Malek
S
S
Van Uden
J
J
Martin-Orozco
E
E
Gelfand
E W
EW
Raz
E
E
D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000627:therapeutic use*; D000281:Administration, Intranasal; D000485:Allergens / Q000633:toxicity*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D001853:Bone Marrow / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D001985:Bronchial Provocation Tests; D018899:CpG Islands; D003888:Desensitization, Immunologic; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004804:Eosinophils / Q000473:pathology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D017681:Hypereosinophilic Syndrome / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D007371:Interferon-gamma / Q000096:biosynthesis; D007377:Interleukin-3 / Q000096:biosynthesis; D015848:Interleukin-5 / Q000096:biosynthesis*; D016210:Methacholine Chloride; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010047:Ovalbumin / Q000276:immunology; D010993:Plethysmography, Whole Body; D011657:Pulmonary Eosinophilia / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D018418:Th2 Cells / Q000276:immunology; D014132:Trachea / Q000473:pathology
D000276:Adjuvants, Immunologic; D000485:Allergens; D000893:Anti-Inflammatory Agents; D007377:Interleukin-3; D015848:Interleukin-5; D009838:Oligodeoxyribonucleotides; D016210:Methacholine Chloride; D003907:Dexamethasone; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D010047:Ovalbumin