House Dust Mite Sublingual Immunotherapy The Role for Transforming Growth Factor–β and Functional Regulatory T Cells

• Published in: American journal of respiratory and critical care medicine Vol. 180; no. 10; pp. 936 - 947
• Main Authors: O'Hehir, Robyn E., Gardner, Leanne M., de Leon, Maria P., Hales, Belinda J., Biondo, Mark, Douglass, Jo A., Rolland, Jennifer M., Sandrini, Alessandra
• Format: Journal Article
• Language: English
• Published: New York, NY American Thoracic Society 15.11.2009
• Subjects: Administration, Sublingual; Adolescent; Adult; Aged; Allergens - administration & dosage; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Asthma - therapy; Biological and medical sciences; Blood. Blood and plasma substitutes. Blood products. Blood cells. Blood typing. Plasmapheresis. Apheresis; Double-Blind Method; Female; Humans; Immunotherapy - methods; Intensive care medicine; Interleukin-5 - biosynthesis; Male; Medical sciences; Middle Aged; Pyroglyphidae - immunology; Respiratory Hypersensitivity - therapy; Rhinitis, Allergic, Perennial - therapy; T-Lymphocytes, Regulatory - immunology; Transforming Growth Factor beta - physiology; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; T lymphocytes; Immunopathology; Allergy; Intensive care; allergen immunotherapy; Transforming growth factor β; Sublingual administration; regulatory T cells; Treatment; transforming growth factor-β; Immunotherapy; T-Lymphocyte; Sublingual; Resuscitation
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.200905-0686OC

Sublingual allergen-specific immunotherapy is gaining popularity for treatment of allergic diseases, but underlying immunological mechanisms are unresolved. To perform detailed immunological investigation of sublingual house dust mite (HDM) immunotherapy. 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. 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. 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).