Background: Ligands triggering TLR7 represent a new group of adjuvants for immunotherapy. We investigated the ability of a synthetic heterocycle [4-(6-amino-9-benzil 8-idrossi-9H-purin-2-ilsulfanil)butirrico 2,5-diossopirrolidin-1-il estere] called SA26E,chemically conjugated to nDer p2, to trigger murine TLR7. We also analyzed the effects of the conjugate in the prevention of airway hyperreactivity (AHR) upon antigen challenge and in the modulation of Th2-mediated immune response in a short and long-term preventative murine model of airway inflammation.Methods: C57Bl/6 mice were i.p. immunized with nDer p2-conjugate at d0 and d7, while control mice with an inert analogue of SA26E. At d14 and d18 mice were intratracheally challenged twice with nDer p2, assessed at d19 for methacolineinduced AHR and then sacrified at d21. In the long-term protocol, mice followed the previous protocol (d0, d7, d14, d18) but were intratracheally challenged six months after the first exposure and sacrified three days later. Results: SA26E, after allergen conjugation, maintained the ability to trigger HEK293 cell line transfected with murine TLR7. Moreover, it significantly inhibited AHR measured as Penh value and suppressed the total number of eosinophils in bronchoalveolar lavage. This effect was associated with a shift in the antibody profile from a type 2- (IgE and IgG1) to a type 1-associated (IgG2a) humoral response. A reduction of IL-13 and a parallel increase of IFN-a˜ production by mononuclear cells obtained by draining lymph nodes upon in vitro antigen stimulation was observed. Interestingly, a concomitant marked increase of IL-10 levels was displayed in both the spleen and draining lymph nodes. Finally, all these results (prevention of lung inflammation, increase of IL-10 and IFN-a˜ production and IgG2a-driven humoral response as well as reduction of IL-13 secretion) were confirmed in the long-term model. Conclusions: These data suggest that the use of nDer p2-SA26E conjugated redirects and regulates the immune response and may constitute an useful approach for immunotherapy of allergic disorders.
Short and long-term effect of a novel nDer p2-conjugated TLR7 ligand in the prevention of allergic lung inflammation / Pratesi S; Petroni G; Vultaggio A; Nencini F; Cardilllicchia E ; Fili L; Casini A; Guarna A; Romagnani S ; Parronchi P ; Maggi E. - In: ALLERGY. - ISSN 0105-4538. - ELETTRONICO. - 67:(2012), pp. 295-295.
Short and long-term effect of a novel nDer p2-conjugated TLR7 ligand in the prevention of allergic lung inflammation
PRATESI, SARA;PETRONI, GIULIA;VULTAGGIO, ALESSANDRA;NENCINI, FRANCESCA;CARDILICCHIA, ELISA;FILI', LUCIA;GUARNA, ANTONIO;ROMAGNANI, SERGIO;PARRONCHI, PAOLA;MAGGI, ENRICO
2012
Abstract
Background: Ligands triggering TLR7 represent a new group of adjuvants for immunotherapy. We investigated the ability of a synthetic heterocycle [4-(6-amino-9-benzil 8-idrossi-9H-purin-2-ilsulfanil)butirrico 2,5-diossopirrolidin-1-il estere] called SA26E,chemically conjugated to nDer p2, to trigger murine TLR7. We also analyzed the effects of the conjugate in the prevention of airway hyperreactivity (AHR) upon antigen challenge and in the modulation of Th2-mediated immune response in a short and long-term preventative murine model of airway inflammation.Methods: C57Bl/6 mice were i.p. immunized with nDer p2-conjugate at d0 and d7, while control mice with an inert analogue of SA26E. At d14 and d18 mice were intratracheally challenged twice with nDer p2, assessed at d19 for methacolineinduced AHR and then sacrified at d21. In the long-term protocol, mice followed the previous protocol (d0, d7, d14, d18) but were intratracheally challenged six months after the first exposure and sacrified three days later. Results: SA26E, after allergen conjugation, maintained the ability to trigger HEK293 cell line transfected with murine TLR7. Moreover, it significantly inhibited AHR measured as Penh value and suppressed the total number of eosinophils in bronchoalveolar lavage. This effect was associated with a shift in the antibody profile from a type 2- (IgE and IgG1) to a type 1-associated (IgG2a) humoral response. A reduction of IL-13 and a parallel increase of IFN-a˜ production by mononuclear cells obtained by draining lymph nodes upon in vitro antigen stimulation was observed. Interestingly, a concomitant marked increase of IL-10 levels was displayed in both the spleen and draining lymph nodes. Finally, all these results (prevention of lung inflammation, increase of IL-10 and IFN-a˜ production and IgG2a-driven humoral response as well as reduction of IL-13 secretion) were confirmed in the long-term model. Conclusions: These data suggest that the use of nDer p2-SA26E conjugated redirects and regulates the immune response and may constitute an useful approach for immunotherapy of allergic disorders.I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.