The helminth product, ES-62, protects against airway inflammation by resetting the Th cell phenotype

Justyna Rzepecka, Ivonne Siebeke, Jennifer Coltherd, Dorothy Kean, Christina Steiger, Lamyaa Al-Riyami, Charles McSharry, Margaret Harnett, William Harnett

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

We previously demonstrated inhibition of ovalbumin (OVA)-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 OVA-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 (Treg) responses (there is no increased IL-10 or Foxp3 expression) but rather a switch in polarisation towards increased T-bet 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.
LanguageEnglish
Pages211–223
Number of pages13
JournalInternational Journal for Parasitology
Volume43
Issue number3-4
DOIs
Publication statusPublished - Mar 2013

Fingerprint

Helminths
Inflammation
Phenotype
Lung
Interleukin-17
Neutrophil Infiltration
Ovalbumin
Mast Cells
Respiratory Hypersensitivity
Acanthocheilonema
Asthma
Steroids
Th1-Th2 Balance
Phosphorylcholine
Eosinophilia
Regulatory T-Lymphocytes
Neutralizing Antibodies
Interleukin-4
Interleukin-10
Immunoglobulin E

Keywords

  • asthma
  • airway inflammation
  • parasitic helminth
  • neutrophil

Cite this

Rzepecka, Justyna ; Siebeke, Ivonne ; Coltherd, Jennifer ; Kean, Dorothy ; Steiger, Christina ; Al-Riyami, Lamyaa ; McSharry, Charles ; Harnett, Margaret ; Harnett, William. / The helminth product, ES-62, protects against airway inflammation by resetting the Th cell phenotype. In: International Journal for Parasitology. 2013 ; Vol. 43, No. 3-4. pp. 211–223.
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Rzepecka, J, Siebeke, I, Coltherd, J, Kean, D, Steiger, C, Al-Riyami, L, McSharry, C, Harnett, M & Harnett, W 2013, 'The helminth product, ES-62, protects against airway inflammation by resetting the Th cell phenotype' International Journal for Parasitology, vol. 43, no. 3-4, pp. 211–223. https://doi.org/10.1016/j.ijpara.2012.12.001

The helminth product, ES-62, protects against airway inflammation by resetting the Th cell phenotype. / Rzepecka, Justyna; Siebeke, Ivonne; Coltherd, Jennifer; Kean, Dorothy ; Steiger, Christina; Al-Riyami, Lamyaa; McSharry, Charles; Harnett, Margaret; Harnett, William.

In: International Journal for Parasitology, Vol. 43, No. 3-4, 03.2013, p. 211–223.

Research output: Contribution to journalArticle

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T1 - The helminth product, ES-62, protects against airway inflammation by resetting the Th cell phenotype

AU - Rzepecka, Justyna

AU - Siebeke, Ivonne

AU - Coltherd, Jennifer

AU - Kean, Dorothy

AU - Steiger, Christina

AU - Al-Riyami, Lamyaa

AU - McSharry, Charles

AU - Harnett, Margaret

AU - Harnett, William

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N2 - We previously demonstrated inhibition of ovalbumin (OVA)-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 OVA-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 (Treg) responses (there is no increased IL-10 or Foxp3 expression) but rather a switch in polarisation towards increased T-bet 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.

AB - We previously demonstrated inhibition of ovalbumin (OVA)-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 OVA-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 (Treg) responses (there is no increased IL-10 or Foxp3 expression) but rather a switch in polarisation towards increased T-bet 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.

KW - asthma

KW - airway inflammation

KW - parasitic helminth

KW - neutrophil

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DO - 10.1016/j.ijpara.2012.12.001

M3 - Article

VL - 43

SP - 211

EP - 223

JO - International Journal for Parasitology

T2 - International Journal for Parasitology

JF - International Journal for Parasitology

SN - 0020-7519

IS - 3-4

ER -