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,
*
Department of Medicine, and
The Sam and Rose Stein Institute for Research on Aging, University of California at San Diego, La Jolla, CA 92093;
Dynavax Technologies Corporation, San Diego, CA 92121; and
§
Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206
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-
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.
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H. Shirota, K. Sano, T. Kikuchi, G. Tamura, and K. Shirato Regulation of T-helper Type 2 Cell and Airway Eosinophilia by Transmucosal Coadministration of Antigen and Oligodeoxynucleotides Containing CpG Motifs Am. J. Respir. Cell Mol. Biol., February 1, 2000; 22(2): 176 - 182. [Abstract] [Full Text]
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Y. Shibata, L. A. Foster, J. F. Bradfield, and Q. N. Myrvik Oral Administration of Chitin Down-Regulates Serum IgE Levels and Lung Eosinophilia in the Allergic Mouse J. Immunol., February 1, 2000; 164(3): 1314 - 1321. [Abstract] [Full Text] [PDF]
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G. Hansen, V. P. Yeung, G. Berry, D. T. Umetsu, and R. H. DeKruyff Vaccination with Heat-Killed Listeria as Adjuvant Reverses Established Allergen-Induced Airway Hyperreactivity and Inflammation: Role of CD8+ T Cells and IL-18 J. Immunol., January 1, 2000; 164(1): 223 - 230. [Abstract] [Full Text] [PDF]
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P. Parronchi, F. Brugnolo, F. Annunziato, C. Manuelli, S. Sampognaro, C. Mavilia, S. Romagnani, and E. Maggi Phosphorothioate Oligodeoxynucleotides Promote the In Vitro Development of Human Allergen-Specific CD4+ T Cells into Th1 Effectors J. Immunol., December 1, 1999; 163(11): 5946 - 5953. [Abstract] [Full Text] [PDF]
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G. Hartmann, G. J. Weiner, and A. M. Krieg CpG DNA: A potent signal for growth, activation, and maturation of human dendritic cells PNAS, August 3, 1999; 96(16): 9305 - 9310. [Abstract] [Full Text] [PDF]
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S. Sur, J. S. Wild, B. K. Choudhury, N. Sur, R. Alam, and D. M. Klinman Long Term Prevention of Allergic Lung Inflammation in a Mouse Model of Asthma by CpG Oligodeoxynucleotides J. Immunol., May 15, 1999; 162(10): 6284 - 6293. [Abstract] [Full Text] [PDF]
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