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House Dust Mite Sublingual Immunotherapy

The Role for Transforming Growth Factor–β and Functional Regulatory T Cells

¹ Department of Allergy, Immunology and Respiratory Medicine, Alfred Hospital, Melbourne, Australia; ² Department of Immunology, Monash University, Melbourne, Australia; and ³ Telethon Institute for Child Health Research, Perth, Australia

Correspondence and requests for reprints should be addressed to Robyn O'Hehir, Ph.D., F.R.A.C.P., Department of Allergy, Immunology and Respiratory Medicine, Alfred Hospital, Commercial Road, Melbourne, VIC 3004, Australia. E-mail: robyn.ohehir{at}med.monash.edu.au

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)-β 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-βRII 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 IgG₄ 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-β 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).

Key Words: allergen immunotherapy • sublingual administration • regulatory T cells • transforming growth factor–β • T lymphocytes

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Although meta-analyses support clinical efficacy of sublingual immunotherapy (SLIT), the strong placebo effect observed in all clinical trials mandates demonstration of unequivocal immunological changes. What This Study Adds to the Field This randomized double-blind placebo-controlled trial of house dust mite SLIT demonstrates that clinically effective SLIT is associated with suppression of allergen-specific T-cell proliferation, immune deviation, and induction of functional Tregs. We demonstrate the pivotal role of the suppressive cytokine transforming growth factor–β as the mediator of early SLIT-induced suppression of the T-cell responses to allergen.