title: House dust mite sublingual immunotherapy: the role for transforming growth factor-beta and functional regulatory T cells.
abstract: BACKGROUND
  Sublingual allergen-specific immunotherapy is gaining popularity for treatment of allergic diseases, but underlying immunological mechanisms are unresolved.
  
  
  OBJECTIVE
  To perform detailed immunological investigation of sublingual house dust mite (HDM) immunotherapy.
  
  
  METHODS
  A 12-month randomized double-blind placebo-controlled study of sublingual HDM immunotherapy in 30 HDM-allergic subjects was performed, with 1-year open extension in 9 patients on active treatment. HDM-stimulated blood mononuclear cells were analyzed for proliferation, cytokines, and regulatory T cells (Tregs) by flow cytometry and ELISA. Effects of blocking transforming growth factor (TGF)-beta and IL-10 on proliferation were determined. Treg suppressor function and allergen-specific antibody levels were measured. Clinical efficacy was assessed by symptom, medication, and Juniper quality-of-life scores.
  
  
  RESULTS
  Allergen-induced CD4(+) T-cell division and IL-5 production were significantly decreased after 6- and 12-months' active treatment but not placebo. sTGF-betaRII blocked immunotherapy-induced suppression of allergen-specific T-cell proliferation, maximal at 6 months. Decreased allergen-specific CD4(+) T-cell proliferation and increased IL-10 secretion and serum Der p 2-specific IgG(4) were maximal at 24 months' active treatment. Treg (CD4(+)CD25(+)CD127(lo)/Foxp3(+)) function was demonstrated by suppression of allergen-specific effector T-cell (CD4(+)CD25(-)CD127(hi)) proliferation and cytokine production. Clinical efficacy of immunotherapy was supported by significantly decreased rhinitis symptom score, total asthma score, and Juniper quality-of-life score.
  
  
  CONCLUSIONS
  This study establishes the novel finding that TGF-beta mediates the immunological suppression seen early in clinically effective sublingual HDM immunotherapy in addition to an increase in Tregs with suppressor function. Clinical trial registered with www.clinicaltrials.gov (NCT00250263).
authors.affiliation: Department of Allergy, Immunology and Respiratory Medicine, Alfred Hospital, Commercial Road, Melbourne, VIC 3004, Australia. robyn.ohehir@med.monash.edu.au
authors.forename: Robyn E
authors.initials: RE
authors.lastname: O'Hehir
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Gardner
authors.forename: Maria P
authors.initials: MP
authors.lastname: de Leon
authors.forename: Belinda J
authors.initials: BJ
authors.lastname: Hales
authors.forename: Mark
authors.initials: M
authors.lastname: Biondo
authors.forename: Jo A
authors.initials: JA
authors.lastname: Douglass
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Rolland
authors.forename: Alessandra
authors.initials: A
authors.lastname: Sandrini
mesh_terms: D000286:Administration, Sublingual; D000293:Adolescent; D000328:Adult; D000368:Aged; D000485:Allergens / Q000008:administration & dosage; D000818:Animals; D001249:Asthma / Q000628:therapy; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D015848:Interleukin-5 / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D039981:Pyroglyphidae / Q000276:immunology*; D012130:Respiratory Hypersensitivity / Q000628:therapy*; D012221:Rhinitis, Allergic, Perennial / Q000628:therapy; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D000485:Allergens; D015848:Interleukin-5; D016212:Transforming Growth Factor beta