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* Center for Research, Transfer and High Education (DENOThe) and
Department of Internal Medicine,
Department of Organic Chemistry "Ugo Schiff",
Department of Dermatological Sciences, and
¶ Department of Anatomy, Histology and Forensic Medicine, University of Florence, Florence, Italy; and
|| Immunobiology Group, Medical Research Council Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
Substitute adenine (SA)-2, a synthetic heterocycle chemically related to adenine with substitutions in positions 9-, 2-, and 8- (i.e., 9-benzyl-2-butoxy-8-hydroxyadenine), induces in vitro immunodeviation of Th2 cells to a Th0/Th1 phenotype. In this article, we evaluate the in vivo ability of SA-2 to affect Th2-mediated lung inflammation and its safety. TLR triggering and NF-
B activation by SA-2 were analyzed on TLR-transfected HEK293 cells and on purified bone marrow dendritic cells. The in vivo effect of SA-2 on experimental airway inflammation was evaluated in both prepriming and prechallenge protocols by analyzing lung inflammation, including tissue eosinophilia and goblet cell hyperplasia, bronchoalveolar lavage fluid cell types, and the functional profile of Ag-specific T cells from draining lymph nodes and spleens. SA-2 induced mRNA expression and production of proinflammatory (IL-6, IL-12, and IL-27) and regulatory (IL-10) cytokines and chemokines (CXCL10) in dendritic cells but down-regulated TGF-β. Prepriming administration of SA-2 inhibited OVA-specific Abs and Th2-driven lung inflammation, including tissue eosinophilia and goblet cells, with a prevalent Foxp3-independent regulatory mechanism. Prechallenge treatment with SA-2 reduced the lung inflammation through the induction of a prevalent Th1-related mechanism. In this model the activity of SA-2 was route-independent, but adjuvant- and Ag dose-dependent. SA-2-treated mice did not develop any increase of serum antinuclear autoantibodies. In conclusion, critical substitutions in the adenine backbone creates a novel synthetic TLR7 ligand that shows the ability to ameliorate Th2-mediated airway inflammation by a complex mechanism, involving Th1 redirection and cytokine-mediated regulation, which prevents autoreactivity.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This research was supported by funds provided by the Italian Ministry of Education, the Italian Ministry of Health, European Union projects (SENS-IT-IV, FP6-LSBH-CT-2006-018861; INNOCHEM, FP6-LSHB-CT-2005-518167), and the Norman Salvesen Emphysema Research Trust (U.K.).
2 Address correspondence and reprint requests to Dr. E. Maggi, Immunoallergology Unit, Center for Research, Transfer and High Education (DENOThe), University of Florence, Policlinico di Careggi, Viale Morgagni, 85, 50134 Florence, Italy. E-mail address: e.maggi{at}dmi.unifi.it
3 Abbreviations used in this paper: DC, dendritic cell; ANA, antinuclear autoantibody; BALF, bronchoalveolar lavage fluid; BMDC, bone marrow-derived DC; CpG-ODN, CpG-containing oligodeoxynucleotide; hd, high dose; i.t., intratracheal; MNC, mononuclear cell; SA, substitute adenine; SA-1, 2-butoxy adenine; SA-2, 9-benzyl-2-butoxy-8-hydroxyadenine; Treg, regulatory T.
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