Modified adenine (9-benzyl-2-butoxy-8-hydroxyadenine) redirects Th2-mediated murine lung inflammation by triggering TLR7.
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-kappaB 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-beta. 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.
Vultaggio
Alessandra
A
Center for Research, Transfer and High Education (DENOThe), Department of Internal Medicine, University of Florence, Florence, Italy.
Nencini
Francesca
F
Fitch
Paul M
PM
Filì
Lucia
L
Maggi
Laura
L
Fanti
Paola
P
deVries
Annick
A
Beccastrini
Enrico
E
Palandri
Francesca
F
Manuelli
Cinzia
C
Bani
Daniele
D
Giudizi
Maria Grazia
MG
Guarna
Antonio
A
Annunziato
Francesco
F
Romagnani
Sergio
S
Maggi
Enrico
E
Howie
Sarah E M
SE
Parronchi
Paola
P
D000208:Acute Disease; D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000502:physiology* / Q000627:therapeutic use; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000502:physiology* / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000627:therapeutic use; D002460:Cell Line; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis / Q000502:physiology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D008171:Lung Diseases / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D000276:Adjuvants, Immunologic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018925:Chemokines; D016207:Cytokines; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D000225:Adenine