title: Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients.
abstract: We previously reported that human CD4+ Tregs secrete high levels of IL-10 when stimulated in the presence of dexamethasone and calcitriol (vitamin D3). We now show that following stimulation by allergen, IL-10-secreting Tregs inhibit cytokine secretion by allergen-specific Th2 cells in an IL-10-dependent manner. A proportion of patients with severe asthma fail to demonstrate clinical improvement upon glucocorticoid therapy, and their asthma is characterized as glucocorticoid resistant (SR, abbreviation derived from "steroid resistant"). Dexamethasone does not enhance secretion of IL-10 by their CD4+ T cells. Addition of vitamin D3 with dexamethasone to cultures of SR CD4+ T cells enhanced IL-10 synthesis to levels observed in cells from glucocorticoid-sensitive patients cultured with dexamethasone alone. Furthermore, pretreatment with IL-10 fully restored IL-10 synthesis in these cells in response to dexamethasone. Vitamin D3 significantly overcame the inhibition of glucocorticoid-receptor expression by dexamethasone while IL-10 upregulated glucocorticoid-receptor expression by CD4+ T cells, suggesting potential mechanisms whereby these treatments may overcome poor glucocorticoid responsiveness. We show here that administration of vitamin D3 to healthy individuals and SR asthmatic patients enhanced subsequent responsiveness to dexamethasone for induction of IL-10. This strongly suggests that vitamin D3 could potentially increase the therapeutic response to glucocorticoids in SR patients.
authors.affiliation: Medical Research Council and Asthma-UK Centre in Allergic Mechanisms of Asthma at King's College London, Strand, London, United Kingdom.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Xystrakis
authors.forename: Siddharth
authors.initials: S
authors.lastname: Kusumakar
authors.forename: Sandra
authors.initials: S
authors.lastname: Boswell
authors.forename: Emma
authors.initials: E
authors.lastname: Peek
authors.forename: Zoë
authors.initials: Z
authors.lastname: Urry
authors.forename: David F
authors.initials: DF
authors.lastname: Richards
authors.forename: Tonye
authors.initials: T
authors.lastname: Adikibi
authors.forename: Carol
authors.initials: C
authors.lastname: Pridgeon
authors.forename: Margaret
authors.initials: M
authors.lastname: Dallman
authors.forename: Tuck-Kay
authors.initials: TK
authors.lastname: Loke
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Robinson
authors.forename: Franck J
authors.initials: FJ
authors.lastname: Barrat
authors.forename: Anne
authors.initials: A
authors.lastname: O'Garra
authors.forename: Paul
authors.initials: P
authors.lastname: Lavender
authors.forename: Tak H
authors.initials: TH
authors.lastname: Lee
authors.forename: Christopher
authors.initials: C
authors.lastname: Corrigan
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Hawrylowicz
mesh_terms: D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002762:Cholecalciferol / Q000627:therapeutic use; D003907:Dexamethasone / Q000627:therapeutic use*; D004351:Drug Resistance / Q000276:immunology*; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism*; D012016:Reference Values
chemical_list: D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D016753:Interleukin-10; D002762:Cholecalciferol; D003907:Dexamethasone