title: Effective treatment of experimental ragweed-induced asthma with STAT-6-IP, a topically delivered cell-penetrating peptide.
abstract: BACKGROUND
  Treatment of allergic airways disease including asthma remains primarily local immunosuppression with topical corticosteroid and symptomatic management with antihistamines and anti-leucotrienes. We have developed a novel topical therapy designed to specifically inhibit the events associated with Th2 cell activation.
  
  
  OBJECTIVE
  We assessed the efficacy of our cell-penetrating STAT-6 inhibitory peptide (STAT-6-IP), a novel treatment for allergic airways disease, in a model of chronic ragweed-induced asthma.
  
  
  METHODS
  Six- to eight-week-old mice were sensitized over 5 weeks with intranasal (IN) exposures to whole ragweed allergen without adjuvant. Mice were then IN challenged with Amba 1 with and without treatment IN with STAT-6-IP and allergic responses assessed. Two weeks later, some animals were rechallenged with Amba 1 with or without STAT-6-IP.
  
  
  RESULTS
  Animals exposed to IN ragweed developed significant airway hyperresponsiveness and airways inflammation upon challenge. Cell cultures showed increases in Th2 cytokines IL-4 and IL-13. Topical STAT-6-IP treatment reduced production of Th2 cytokines, demonstrated increased expression of IL-10 and reduced frequency of cultured IL-4 positive CD4+ T cells derived from treated mice, suggesting that STAT-6-IP treatment may be immunomodulatory. Airway responsiveness to methacholine challenge in the treatment group was similarly reduced to that of the non-allergic PBS-exposed animals. Importantly, STAT-6-IP-treated mice remained hyporesponsive following second ragweed challenge 2 weeks after treatment.
  
  
  CONCLUSIONS
  These data suggest that topical application of the STAT-6-IP is sufficient to inhibit allergic airways responses in animals chronically sensitized and challenged with ragweed. Data show that a single topical treatment course is sufficient to block signs of allergic responses to ragweed in the airways for at least 2 weeks. STAT-6-IP is a novel potential treatment for chronic allergic asthma.
authors.affiliation: Meakins-Christie Laboratories, McGill University Health Center Research Institute, Montreal, QC, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: J
authors.initials: J
authors.lastname: Shan
authors.forename: E
authors.initials: E
authors.lastname: Fixman
authors.forename: C
authors.initials: C
authors.lastname: McCusker
mesh_terms: D000287:Administration, Topical; D031164:Ambrosia / Q000276:immunology*; D000818:Animals; D052179:Antigens, Plant / Q000008:administration & dosage / Q000276:immunology*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology*; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D004195:Disease Models, Animal; D007073:Immunoglobulin E / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D010748:Phosphopeptides / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D050800:STAT6 Transcription Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology
chemical_list: D052179:Antigens, Plant; D057846:Cell-Penetrating Peptides; D007074:Immunoglobulin G; D009842:Oligopeptides; D010748:Phosphopeptides; C573337:STAT-6 inhibitor peptide; D050800:STAT6 Transcription Factor; D007073:Immunoglobulin E