title: Defective IL-10 expression and in vitro steroid-induced IL-17A in paediatric severe therapy-resistant asthma.
abstract: BACKGROUND
  Understanding of immune mechanisms underpinning asthma has emerged from studies in adults. It is increasingly recognised, both immunologically and in the development of novel therapies, that adult responses cannot be used accurately to predict those of children.
  
  
  METHODS
  Using a well-defined paediatric cohort of severe therapy-resistant asthma (STRA) patients, we investigated cytokine profiles in the airway by analysis of bronchoalveolar lavage fluid. The in vitro capacity of peripheral blood mononuclear cells (PBMCs) for cytokine production was also assessed following polyclonal T cell activation in culture, in the absence or presence of dexamethasone and 1α,25-dihydroxyvitamin D3.
  
  
  RESULTS
  Children with both moderate and STRA had significantly diminished levels of anti-inflammatory interleukin (IL)-10 in airway lavage samples when compared with non-asthmatic controls (p<0.001). Their PBMCs also demonstrated significantly impaired capacity to secrete IL-10 in culture (p<0.001). Dexamethasone regulated the balance between PBMC IL-10 and IL-13 production, increasing IL-10 secretion (p<0.001) and decreasing IL-13 (p<0.001) but unexpectedly enhanced IL-17A production in all groups-most strikingly in the STRA cohort (p<0.001). The inclusion of the active form of vitamin D, 1α,25-dihydroxyvitamin D3, in culture enhanced dexamethasone-induced IL-10 (p<0.05) without marked effects on IL-13 or IL-17A production. Furthermore, systemic vitamin D status directly correlated with airway IL-10 (r=0.6, p<0.01).
  
  
  CONCLUSIONS
  These findings demonstrate reduced peripheral and local IL-10 synthesis in paediatric asthma, and support therapeutic augmentation of low circulating vitamin D in severe, difficult-to-treat asthma, in order to correct impaired IL-10 levels. Conversely, steroids enhanced IL-17A levels, and therefore any steroid-sparing properties of vitamin D may have additional benefit in STRA.
authors.affiliation: MRC & Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London, Guy's Hospital, London, UK Department of Pediatric Respiratory Medicine, Imperial College London, London, UK.
authors.forename: Atul
authors.initials: A
authors.lastname: Gupta
authors.affiliation: MRC & Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London, Guy's Hospital, London, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Dimeloe
authors.affiliation: MRC & Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London, Guy's Hospital, London, UK.
authors.forename: David F
authors.initials: DF
authors.lastname: Richards
authors.affiliation: MRC & Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London, Guy's Hospital, London, UK.
authors.forename: Emma S
authors.initials: ES
authors.lastname: Chambers
authors.affiliation: MRC & Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London, Guy's Hospital, London, UK.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Black
authors.affiliation: MRC & Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London, Guy's Hospital, London, UK.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Urry
authors.affiliation: MRC & Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London, Guy's Hospital, London, UK.
authors.forename: Kimuli
authors.initials: K
authors.lastname: Ryanna
authors.affiliation: MRC & Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London, Guy's Hospital, London, UK.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Xystrakis
authors.affiliation: MRC & Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London, Guy's Hospital, London, UK Department of Pediatric Respiratory Medicine, Imperial College London, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bush
authors.affiliation: MRC & Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London, Guy's Hospital, London, UK Department of Pediatric Respiratory Medicine, Imperial College London, London, UK.
authors.forename: Sejal
authors.initials: S
authors.lastname: Saglani
authors.affiliation: MRC & Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London, Guy's Hospital, London, UK.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Hawrylowicz
mesh_terms: D000293:Adolescent; D001249:Asthma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016022:Case-Control Studies; D002648:Child; D003907:Dexamethasone / Q000494:pharmacology; D004351:Drug Resistance; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D016753:Interleukin-10 / Q000096:biosynthesis*; D018793:Interleukin-13 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D013601:T-Lymphocytes / Q000276:immunology; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D005938:Glucocorticoids; D018793:Interleukin-13; D020381:Interleukin-17; C118756:dihydroxy-vitamin D3; D016753:Interleukin-10; D014807:Vitamin D; D007073:Immunoglobulin E; D003907:Dexamethasone