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P193 A role for active Vitamin D in steroid resistant asthma patients who have enhanced production of IL-17A and reduced IL-10
  1. AM Nanzer1,
  2. ES Chambers1,
  3. DF Richards1,
  4. AR Martineau2,
  5. CJ Griffiths2,
  6. C Corrigan1,
  7. CM Hawrylowicz1
  1. 1MRC and Asthma UK Centre for Allergic Mechanisms in Asthma, King’s College London, London, UK
  2. 2Centre for Primary Care and Public Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK

Abstract

Background Steroid refractory (SR) asthma, a distinct disease phenotype, has a high morbidity and mortality and takes up a disproportional burden of healthcare cost. IL-17A is a pro-inflammatory cytokine that is essential for host defence against pathogens but can also lead to damage of the surrounding tissues associated with immune diseases and is linked with severe asthma. IL-10 has crucial immunregulatory properties, and we have previously shown in vitro, that T cells from steroid refractory asthma patients fail to respond to glucocorticosteroids for the induction of IL-10 synthesis.

Methods We assessed IL-17A and IL-10 synthesis in steroid sensitive, SS, (mean% change in FEV1 following 2 weeks of oral prednisolone 16%) versus SR (mean% change FEV1 0%) asthma patients and investigated their response to dexamethasone.

Results PBMC from SR individuals synthesised 7-fold higher levels of IL-17A than disease-severity matched SS patients (by flow cytometry and CBA). Interestingly IL-17A levels inversely correlated with changes in lung function following oral steroids whereas higher IL-10 levels were associated with an increase in lung function. Dexamethasone failed to inhibit IL-17A, but, surprisingly, increased protein synthesis, an effect that was also seen in vivo: inhaled glucocorticosteroid dosages correlated with IL-17A protein levels. This suggests the potentially detrimental effects corticosteroids might have in certain asthma phenotypes. The production of IL-10 by T cells was impaired in cultures from SR asthmatics, but not in healthy controls or SS asthma patients implying an associated impaired IL-10 response with poor asthma control. 1alpha,25-dihydroxyvitamin D3 (1,25(OH)D) not only restored the capacity of T cells to produce IL-10 upon stimulation with dexamethasone in SR asthma patients, but also inhibited IL-17A synthesis in culture independently of steroid.

Conclusion High IL-17A levels are associated with poor response to steroids and more severe asthma. Our data supports a steroid-enhancing property of 1,25(OH)D in severe asthma through inhibition of IL-17A and via enhancement of IL-10 synthesis.

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