title: The helminth product, ES-62, protects against airway inflammation by resetting the Th cell phenotype.
abstract: We previously demonstrated inhibition of ovalbumin-induced allergic airway hyper-responsiveness in the mouse using ES-62, a phosphorylcholine-containing glycoprotein secreted by the filarial nematode, Acanthocheilonema viteae. This inhibition correlated with ES-62-induced mast cell desensitisation, although the degree to which this reflected direct targeting of mast cells remained unclear as suppression of the Th2 phenotype of the inflammatory response, as measured by eosinophilia and IL-4 levels in the lungs, was also observed. We now show that inhibition of the lung Th2 phenotype is reflected in ex vivo analyses of draining lymph node recall cultures and accompanied by a decrease in the serum levels of total and ovalbumin-specific IgE. Moreover, ES-62 also suppresses the lung infiltration by neutrophils that is associated with severe asthma and is generally refractory to conventional anti-inflammatory therapies, including steroids. Protection against Th2-associated airway inflammation does not reflect induction of regulatory T cell responses (there is no increased IL-10 or Foxp3 expression) but rather a switch in polarisation towards increased Tbet expression and IFNγ production. This ES-62-driven switch in the Th1/Th2 balance is accompanied by decreased IL-17 responses, a finding in line with reports that IFNγ and IL-17 are counter-regulatory. Consistent with ES-62 mediating its effects via IFNγ-mediated suppression of pathogenic Th2/Th17 responses, we found that neutralising anti-IFNγ antibodies blocked protection against airway inflammation in terms of pro-inflammatory cell infiltration, particularly by neutrophils, and lung pathology. Collectively, these studies indicate that ES-62, or more likely small molecule analogues, could have therapeutic potential in asthma, in particular for those subtypes of patients (e.g. smokers, steroid-resistant) who are refractory to current treatments.
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.
authors.forename: Justyna
authors.initials: J
authors.lastname: Rzepecka
authors.forename: Ivonne
authors.initials: I
authors.lastname: Siebeke
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Coltherd
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Kean
authors.forename: Christina N
authors.initials: CN
authors.lastname: Steiger
authors.forename: Lamyaa
authors.initials: L
authors.lastname: Al-Riyami
authors.forename: Charles
authors.initials: C
authors.lastname: McSharry
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Harnett
authors.forename: William
authors.initials: W
authors.lastname: Harnett
mesh_terms: D000818:Animals; D005260:Female; D015801:Helminth Proteins / Q000276:immunology / Q000627:therapeutic use*; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D020011:Protective Agents / Q000627:therapeutic use*; D012130:Respiratory Hypersensitivity / Q000188:drug therapy* / Q000276:immunology* / Q000517:prevention & control; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology*; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology*
chemical_list: C435884:ES-62 protein, Acanthocheilonema viteae; D015801:Helminth Proteins; D020381:Interleukin-17; D020011:Protective Agents; D016753:Interleukin-10; D015847:Interleukin-4