The role of Foxp3+ T cells in long-term efficacy of prophylactic and therapeutic mucosal tolerance induction in mice.
BACKGROUND
Mucosal tolerance induction is suggested as treatment strategy for allergic diseases. Using a murine model of birch pollen (BP) allergy we investigated the long-term efficacy and the underlying mechanisms of mucosal tolerance induction with two structurally different molecules in a prophylactic and in a therapeutic set-up.


METHODS
The three-dimensional major BP allergen Bet v 1 or a nonconformational hypoallergenic fragment thereof was intranasally applied before (prophylaxis) or after sensitization (therapy).


RESULTS
In the prophylactic application both the Bet v 1 allergen and the fragment prevented allergic sensitization, and this effect lasted for 1 year. In the therapeutic approach established allergic immune responses were also suppressed after treatment with either of the molecules. However, a long-lasting curative effect (6 months) was only achieved with the Bet v 1 allergen but not with the Bet v 1 fragment. Real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis of splenocytes revealed that tolerance induction with the Bet v 1 allergen was associated with enhanced expression of transforming growth factor (TGF)-beta, interleukin (IL)-10, and Foxp3 mRNA in CD4+ T cells, whereas treatment with the fragment led to the induction of either Foxp3 (prophylaxis) or IL-10 (therapy) alone.


CONCLUSIONS
From these data we concluded (i) that the mechanisms underlying peripheral tolerance are linked to the conformation of the antigen, (ii) that mucosal tolerance is mediated by separate regulatory cell subsets, and (iii) that the long-term efficacy of immunosuppression is associated with the presence of Foxp3+ T cells.
Winkler
B
B
Department of Specific Prophylaxis and Tropical Medicine, Center for Physiology and Pathophysiology, Medical University of Vienna, Vienna, Austria.
Hufnagl
K
K
Spittler
A
A
Ploder
M
M
Kállay
E
E
Vrtala
S
S
Valenta
R
R
Kundi
M
M
Renz
H
H
Wiedermann
U
U
D000281:Administration, Intranasal; D000485:Allergens / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology; D000818:Animals; D029662:Betula / Q000276:immunology; D003888:Desensitization, Immunologic; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009297:Nasal Mucosa / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D011058:Pollen / Q000737:chemistry / Q000276:immunology; D012333:RNA, Messenger; D020133:Reverse Transcriptase Polymerase Chain Reaction; D006255:Rhinitis, Allergic, Seasonal / Q000517:prevention & control*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000276:immunology
D000485:Allergens; D018984:Epitopes, T-Lymphocyte; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D010446:Peptide Fragments; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D016753:Interleukin-10