House dust mite sublingual immunotherapy: the role for transforming growth factor-beta and functional regulatory T cells.
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).
O'Hehir
Robyn E
RE
Department of Allergy, Immunology and Respiratory Medicine, Alfred Hospital, Commercial Road, Melbourne, VIC 3004, Australia. robyn.ohehir@med.monash.edu.au
Gardner
Leanne M
LM
de Leon
Maria P
MP
Hales
Belinda J
BJ
Biondo
Mark
M
Douglass
Jo A
JA
Rolland
Jennifer M
JM
Sandrini
Alessandra
A
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*
D000485:Allergens; D015848:Interleukin-5; D016212:Transforming Growth Factor beta