BACKGROUND AND PURPOSE Allergic conjunctivitis is an eye inflammation that involves the infiltration of immune cells into the conjunctiva via cell surfaceadhesion receptors, such as integrin α4β1. These receptors interact with adhesion molecules expressed on the conjunctival endothelium and may be a target to treat this disease. We synthesized DS-70, a novel α/β-peptidomimetic α4 integrin antagonist, to prevent the conjunctival infiltration of immune cells and clinical symptoms in a model of allergic conjunctivitis. EXPERIMENTAL APPROACH In vitro, DS-70 was pharmacologically characterized using a scintillation proximity procedure to measure its affinity for α4β1 integrin, and its effect on cell adhesion mediated by different integrins was also evaluated. The effects of DS-70 on vascular cell adhesion molecule-1 (VCAM-1)-mediated degranulation of a human mast cell line and an eosinophilic cell line, which both express α4β1, and on VCAM-1-mediated phosphorylation of ERK 1/2 in Jurkat E6.1 cells were investigated. Effects of DS-70 administered in the conjunctival fornix of ovalbumin-sensitized guinea pigs were evaluated. KEY RESULTS DS-70 bound to integrin α4β1 with nanomolar affinity, prevented the adhesion of α4 integrin-expressing cells, antagonized VCAM-1- mediated degranulation of mast cells and eosinophils and ERK 1/2 phosphorylation. Only 20% was degraded after an 8 h incubation with serum. DS-70 dose-dependently reduced the clinical symptoms of allergic conjunctivitis, conjunctival α4 integrin expression and conjunctival levels of chemokines and cytokines in ovalbumin-sensitized guinea pigs. CONCLUSIONS AND IMPLICATIONS These findings highlight the role of α4 integrin in allergic conjunctivitis and suggest that DS-70 is a potential treatment for this condition.

. DS-70, a novel and potent 4 integrin antagonist, is an effective treatment for experimental allergic conjunctivitis in guinea pigs

Rossella De Marco;
2018-01-01

Abstract

BACKGROUND AND PURPOSE Allergic conjunctivitis is an eye inflammation that involves the infiltration of immune cells into the conjunctiva via cell surfaceadhesion receptors, such as integrin α4β1. These receptors interact with adhesion molecules expressed on the conjunctival endothelium and may be a target to treat this disease. We synthesized DS-70, a novel α/β-peptidomimetic α4 integrin antagonist, to prevent the conjunctival infiltration of immune cells and clinical symptoms in a model of allergic conjunctivitis. EXPERIMENTAL APPROACH In vitro, DS-70 was pharmacologically characterized using a scintillation proximity procedure to measure its affinity for α4β1 integrin, and its effect on cell adhesion mediated by different integrins was also evaluated. The effects of DS-70 on vascular cell adhesion molecule-1 (VCAM-1)-mediated degranulation of a human mast cell line and an eosinophilic cell line, which both express α4β1, and on VCAM-1-mediated phosphorylation of ERK 1/2 in Jurkat E6.1 cells were investigated. Effects of DS-70 administered in the conjunctival fornix of ovalbumin-sensitized guinea pigs were evaluated. KEY RESULTS DS-70 bound to integrin α4β1 with nanomolar affinity, prevented the adhesion of α4 integrin-expressing cells, antagonized VCAM-1- mediated degranulation of mast cells and eosinophils and ERK 1/2 phosphorylation. Only 20% was degraded after an 8 h incubation with serum. DS-70 dose-dependently reduced the clinical symptoms of allergic conjunctivitis, conjunctival α4 integrin expression and conjunctival levels of chemokines and cytokines in ovalbumin-sensitized guinea pigs. CONCLUSIONS AND IMPLICATIONS These findings highlight the role of α4 integrin in allergic conjunctivitis and suggest that DS-70 is a potential treatment for this condition.
File in questo prodotto:
File Dimensione Formato  
British Journal of Pharmacology 2018.pdf

accesso aperto

Descrizione: Articolo principale
Tipologia: Versione Editoriale (PDF)
Licenza: Creative commons
Dimensione 1.69 MB
Formato Adobe PDF
1.69 MB Adobe PDF Visualizza/Apri
British Journal Pharmacology supporting information 2018.pdf

accesso aperto

Descrizione: tabelle dei dati sperimentali
Tipologia: Versione Editoriale (PDF)
Licenza: Creative commons
Dimensione 776.99 kB
Formato Adobe PDF
776.99 kB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11390/1188074
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 23
  • ???jsp.display-item.citation.isi??? 21
social impact