Amb a 1-linked CpG oligodeoxynucleotides reverse established airway hyperresponsiveness in a murine model of asthma.
BACKGROUND
Recently, it has been demonstrated that immunostimulatory DNA sequences (ISS) containing CpG motifs prevent the development of allergic airway responses in murine models of disease. However, few studies have addressed the issue of whether these agents will reverse established Tm(H)2-driven allergic airway responses.


OBJECTIVE
The aim of this study was to determine whether intradermal delivery of an immunogenic protein of ragweed pollen linked to an immunostimulatory DNA sequence could reverse an established allergic response in the mouse lung.


METHODS
Mice sensitized and challenged with ragweed pollen extract were treated intradermally twice at 1-week intervals with an ISS chemically linked to Amb a 1 (Amb a 1-ISS). One week after the Amb a 1-ISS treatment, mice were rechallenged intratracheally with ragweed extract, and airway responses were assessed.


RESULTS
Amb a 1-ISS treatment of ragweed-sensitized and ragweed-challenged mice significantly reversed allergen-induced airway hyperresponsiveness and suppressed the total number of eosinophils in bronchoalveolar lavage fluid. The inhibitory effect of Amb a 1-ISS was associated with a marked increase in IFN-gamma levels by Amb a 1-stimulated splenocytes and a shift in the antibody profile from a T(H)2-directed IgG1 response to a T(H)1-directed IgG2a response. Interestingly, the inhibitory effect of Amb a 1-ISS on allergen-driven airway hyperresponsiveness was independent of suppression of T(H)2 cytokine production.


CONCLUSIONS
These results demonstrate that intradermal delivery of allergen-specific DNA conjugates can reverse established allergic responses in the murine lung, supporting their potential use in the treatment of human asthma.
Santeliz
Joanna V
JV
Department of Environmental Health Sciences, Johns Hopkins School of Hygiene and Public Health, Baltimore, MD, USA.
Van Nest
Gary
G
Traquina
Paula
P
Larsen
Elizabeth
E
Wills-Karp
Marsha
M
D000276:Adjuvants, Immunologic; D000485:Allergens / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use* / Q000633:toxicity; D000818:Animals; D052179:Antigens, Plant; D019659:Asteraceae / Q000276:immunology; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D018899:CpG Islands / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006969:Hypersensitivity, Immediate / Q000188:drug therapy / Q000209:etiology / Q000276:immunology; D007167:Immunotherapy / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000276:immunology*; D010940:Plant Proteins / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use* / Q000633:toxicity; D011058:Pollen / Q000009:adverse effects / Q000276:immunology
D000276:Adjuvants, Immunologic; D000485:Allergens; C026967:Amb a I protein, Ambrosia artemisiifolia; D052179:Antigens, Plant; C408982:CPG-oligonucleotide; D016207:Cytokines; D009838:Oligodeoxyribonucleotides; D010940:Plant Proteins