Prolonged Inhaled Allergen Exposure Can Induce Persistent Tolerance

Chronic innocuous aeroallergen exposure attenuates CD4+ T cell-mediated airways hyperresponsiveness in mice; however, the mechanism(s) remain unclear. We examined the role of airway mucosal dendritic cell (AMDC) subsets in this process using a multi-OVA aerosol-induced tolerance model in sensitized BALB/c mice. Aeroallergen capture by both CD11blo and CD11bhi AMDC and the delivery of OVA to airway draining lymph nodes by CD8α− migratory dendritic cells (DC) were decreased in vivo (but not in vitro) when compared with sensitized but nontolerant mice. This was functionally significant, because in vivo proliferation of OVA-specific CD4+ T cells was suppressed in airway draining lymph nodes of tolerized mice and could be restored by intranasal transfer of OVA-pulsed and activated exogenous DC, indicating a deficiency in Ag presentation by endogenous DC arriving from the airway mucosa. Bone marrow-derived DC Ag-presenting function was suppressed in multi-OVA tolerized mice, and allergen availability to airway APC populations was limited after multi-OVA exposure, as indicated by reduced OVA and dextran uptake by airway interstitial macrophages, with diffusion rather than localization of OVA across the airway mucosal surface. These data indicate that inhalation tolerance limits aeroallergen capture by AMDC subsets through a mechanism of bone marrow suppression of DC precursor function coupled with reduced Ag availability in vivo at the airway mucosa, resulting in limited Ag delivery to lymph nodes and hypoproliferation of allergen-specific CD4+ T cells.

Section: Discussionsupporting

confidence: 94%

Section: Endritic Cells (Dc)mentioning

confidence: 80%

Section: Endritic Cells (Dc)mentioning

confidence: 99%

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Restricted Aeroallergen Access to Airway Mucosal Dendritic Cells In Vivo Limits Allergen-Specific CD4+ T Cell Proliferation during the Induction of Inhalation Tolerance

Fear

Burchell

Lai

et al. 2011

“…immunization adsorbed to alum to achieve sensitization. Moreover, repeated airway administrations with OVA were shown to induce a gradual loss of the asthmatic phenotype in sensitized mice (34)(35)(36), although this effect is not Ag specific. We observed a limited reduction in eosinophilic airway inflammation in mice receiving two series of three OVA inhalations compared with mice that received only a single series of three OVAinhalation challenges ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Suppression of Th2-Driven Airway Inflammation by Allergen Immunotherapy Is Independent of B Cell and Ig Responses in Mice

Shirinbak

Taher

Maazi

et al. 2010

Allergen-specific immunotherapy (IT) uniquely renders long-term relief from allergic symptoms and is associated with elevated serum levels of allergen-specific IgG and IgA. The allergen-specific IgG response induced by IT treatment was shown to be critical for suppression of the immediate phase of the allergic response in mice, and this suppression was partially dependent on signaling through FcγRIIB. To investigate the relevance of the allergen-specific IgG responses for suppression of the Th2-driven late-phase allergic response, we performed IT in a mouse model of allergic asthma in the absence of FcγRIIB or FcγRI/FcγRIII signaling. We found that suppression of Th2 cell activity, allergic inflammation, and allergen-specific IgE responses is independent of FcγRIIB and FcγRI/FcγRIII signaling. Moreover, we show that the IT-induced allergen-specific systemic IgG or IgA responses and B cell function are dispensable for suppression of the late-phase allergic response by IT treatment. Finally, we found that the secretory mucosal IgA response also is not required for suppression of the Th2-driven allergic inflammation by IT. These data are in contrast to the suppression of the immediate phase of the allergic response, which is critically dependent on the induced allergen-specific serum IgG response. Hence, IT-induced suppression of the immediate and late phases of the allergic response is governed by divergent and independent mechanisms. Our data show that the IT-induced suppression of the Th2 cell-dependent late-phase allergic response is independent of the allergen-specific IgG and IgA responses that are associated with IT treatment.

“…Male mice (6-8 wk old) were exposed to OVA, as previously described (11). Briefly, mice were sensitized with 10 mg OVA (grade V; Sigma-Aldrich, Bornem, Belgium) adsorbed to 1 mg Al(OH) 3 (Sigma-Aldrich) i.p.…”

Section: Ova Exposure Modelmentioning

confidence: 99%

P2Y2 Receptor Regulates VCAM-1 Membrane and Soluble Forms and Eosinophil Accumulation during Lung Inflammation

Vanderstocken

Bondue

Horckmans

et al. 2010

ATP has been defined as a key mediator of asthma. In this study, we evaluated lung inflammation in mice deficient for the P2Y2 purinergic receptor. We observed that eosinophil accumulation, a distinctive feature of lung allergic inflammation, was defective in OVA-treated P2Y2-deficient mice compared with OVA-treated wild type animals. Interestingly, the upregulation of VCAM-1 was lower on lung endothelial cells of OVA-treated P2Y2−/− mice compared with OVA-treated wild type animals. Adhesion assays demonstrated that the action of UTP on leukocyte adhesion through the regulation of endothelial VCAM-1 was abolished in P2Y2-deficient lung endothelial cells. Additionally, the level of soluble VCAM-1, reported as an inducer of eosinophil chemotaxis, was strongly reduced in the bronchoalveolar lavage fluid (BALF) of P2Y2-deficient mice. In contrast, we observed comparable infiltration of macrophages and neutrophils in the BALF of LPS-aerosolized P2Y2+/+ and P2Y2−/− mice. This difference could be related to the much lower level of ATP in the BALF of LPS-treated mice compared with OVA-treated mice. Our data define P2Y2 as a regulator of membrane and soluble forms of VCAM-1 and eosinophil accumulation during lung inflammation.