Regulatory T Cells Contribute to Allergen Tolerance Induced by Daily Airway Immunostimulant Exposures

Abstract

Endotoxin and other immunostimulants ubiquitous in ambient air are potent mucosal adjuvants, yet only a minority of individuals develop aeroallergen hypersensitivities, whereas the majority develop tolerance. These investigations were performed to reconcile this paradox. During initial experiments, mice received a primary series of weekly intranasal OVA immunizations (1(0) vaccination). Selected mice also received intranasal sterile house dust extract (HDE) with each OVA vaccination, at a dose previously found to exert adjuvant activity. A third group of OVA-vaccinated mice received intranasal HDE on a daily basis, but at one seventh the adjuvant dose, beginning 1 week before the first and ending with the last 1(0) OVA vaccination. Mice were then left untreated for 4 weeks, and then received a secondary series of weekly intranasal OVA immunizations with adjuvant doses of HDE (2(0) sensitization). Three weeks later, OVA-specific airway challenges and immune responses were assessed. Analogous experiments were conducted with LPS. Mice receiving daily intranasal HDE or LPS during 1(0) OVA vaccination were highly resistant to 2(0) sensitization, whereas the mice in other experimental groups readily developed Th2-biased airway hypersensitivity. Tolerance was associated with poor OVA-specific CD4 cell proliferation and with local natural T-regulatory cell (Treg) expansion. Finally, Treg depletion by delivery of the anti-CD25 monoclonal antibody during 1(0) vaccination attenuated the tolerogenic effects of daily airway HDE exposures. These studies suggest that regular airway immunostimulant exposures selectively increase local Treg numbers and activity in an antigen-independent manner, thereby promoting the development of aeroallergen tolerance.

House dust bioactivities predict skin prick test reactivity for children with high risk of allergy

“…19,20 In analogous experiments LPS, Pam-3-Cys (TLR2), and CpG motifs (TLR9) shared this tolerogenic potential with HDEs (unpublished data). 19,20 These observations might help explain why farm homes and other living environments that contain high concentrations of microbial products protect against atopy. Moreover, they suggest that the relative protective influence of living environments on the genesis of allergic diseases might be far more dependent on their total immunostimulatory load than on their specific content of individual molecules.…”

“…When mice received intranasal vaccinations with ovalbumin (OVA) and HDE at weekly intervals, all doses and HDEs tested (n = 10 homes) were found to induce OVA-specific T H 2-biased airway hypersensitivities. 19 In contrast, if mice received weekly intranasal OVA immunizations, as in previously described studies, while HDE was intranasally delivered daily at a lower dose beginning 1 week before the first and ending with the last OVA immunization, 19,20 mice had long-lived OVA tolerance by mechanisms that were regulatory T (Treg) cell dependent. 19,20 Moreover, daily airway HDE exposures were found to selectively induce IL-10 production and the recruitment, expansion, or both of natural Treg cells in the lungs and bronchial lymph nodes of mice.…”

“…19,20 However, in a murine model more reflective of daily environmental immunostimulant exposures, mice exposed to HDEs through the airways on a daily basis had long-lived allergen tolerance. 19,20 In analogous experiments LPS, Pam-3-Cys (TLR2), and CpG motifs (TLR9) shared this tolerogenic potential with HDEs (unpublished data).…”

“…19,20 However, in a murine model more reflective of daily environmental immunostimulant exposures, mice exposed to HDEs through the airways on a daily basis had long-lived allergen tolerance. 19,20 In analogous experiments LPS, Pam-3-Cys (TLR2), and CpG motifs (TLR9) shared this tolerogenic potential with HDEs (unpublished data). 19,20 These observations might help explain why farm homes and other living environments that contain high concentrations of microbial products protect against atopy.…”

Maternal allergy increases susceptibility to offspring allergy in association with TH2-biased epigenetic alterations in a mouse model of peanut allergy

“…To measure serum peanut-specific IgE, serum IgG antibodies were first depleted by protein G–Sepharose (BioVisio, Milpitas, CA) centrifugation. (35;36) In brief, equal volumes of protein G–Sepharose and undiluted mouse serum were mixed and incubated at room temperature for 10 minutes, then centrifuged at 1200 rpm for 10 minutes at room temperature. Supernatants were collected and the process was repeated twice.…”