House dust mite sublingual immunotherapy: the role for transforming growth factor-beta and functional regulatory T cells

Am J Respir Crit Care Med. 2009 Nov 15;180(10):936-47. doi: 10.1164/rccm.200905-0686OC. Epub 2009 Aug 20.


Rationale: Sublingual allergen-specific immunotherapy is gaining popularity for treatment of allergic diseases, but underlying immunological mechanisms are unresolved.

Objectives: 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.

Measurements and main 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 (NCT00250263).

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Sublingual
  • Adolescent
  • Adult
  • Aged
  • Allergens / administration & dosage
  • Animals
  • Asthma / therapy
  • Double-Blind Method
  • Female
  • Humans
  • Immunotherapy / methods*
  • Interleukin-5 / biosynthesis
  • Male
  • Middle Aged
  • Pyroglyphidae / immunology*
  • Respiratory Hypersensitivity / therapy*
  • Rhinitis, Allergic, Perennial / therapy
  • T-Lymphocytes, Regulatory / immunology*
  • Transforming Growth Factor beta / physiology*


  • Allergens
  • Interleukin-5
  • Transforming Growth Factor beta

Associated data