Chronic Inhaled Ovalbumin Exposure Induces Antigen-Dependent but Not Antigen-Specific Inhalational Tolerance in a Murine Model of Allergic Airway Disease

Abstract

Sensitized mice acutely challenged with inhaled ovalbumin (OVA) develop allergic airway inflammation, characterized by OVA-specific IgE production, airway eosinophilia, increased pulmonary B and T lymphocytes, and airway hyperreactivity. In this study, a chronic exposure model was developed and two distinct patterns of response were observed. Discontinuous inhalational exposure to OVA (6 weeks) produced airway inflammation and hyperreactivity that were similar to acute (10 days) responses. Continuous inhalational exposure to OVA (6 or 11 weeks) resulted in attenuation of airway eosinophilia and hyperresponsiveness without reduction of OVA-specific IgE and IgG 1 levels. The inhibition of airway inflammation was dependent on continuous exposure to antigen, because continuously exposed mice with attenuated inflammatory responses redeveloped allergic airway disease if the OVA aerosols were interrupted and then restarted (11-week-discontinuous). Inhalational tolerance induced by continuous OVA exposure demonstrated bystander suppression of cockroach allergen-mediated airway eosinophilia. These findings may be attributed to changes in production of the anti-inflammatory cytokine interleukin-10 during continuous OVA aerosol exposure. The symptomatic and asymptomatic allergic responses in human asthmatics could be explained by similar variable or discontinuous exposures to aeroantigens. Throughout the past 40 years, the prevalence of allergic disease, including atopic dermatitis, hay fever, and asthma, has risen dramatically in the developed world. This disturbing trend is documented best for asthma. 1,2 A wealth of clinical and experimental data suggests that allergic asthma is due to an aberrant lung immune response mediated through T-helper type 2 cells (Th2 cells) and associated cytokine-signaling pathways. The normal lung is able to distinguish between airborne antigens associated with infectious agents, to which an immunological response is generated, and harmless inhaled antigens, which are usually ignored. In the asthmatic lung, some of these normally harmless antigens activate specific Th2 cells and elicit an inflammatory response characterized by Th2 cytokine production, eosinophilic airway inflammation, airway hyperresponsiveness, and bronchoconstriction. These pulmonary responses may be accompanied by systemic allergic sensitization, manifested by elevated titers of antigen-specific IgE. The mechanisms that control CD4 ϩ T lymphocyte polarization to allergenic Th2 phenotypes are incompletely understood but seem to involve genetic predispositions, local factors such as pre-existing cytokine concentrations and inflammation, and antigenic factors (ie, potency, dose, and duration of exposure).Several investigators have used mouse models to investigate the mechanisms of inhalational tolerance to antigens 3,4 or of allergic airway sensitization. [5][6][7][8][9][10] However, these responses have typically been assessed in isolation from each other. We have recently demonstrated that C57BL/6J mice undergo a biphasic...

Maternal Transmission of Resistance to Development of Allergic Airway Disease

“…Parameters of disease severity are virtually indistinguishable following the primary (acute) or secondary (discontinuous) airway challenge. These results indicate that immunological memory specific for OVA exists in mice at 4 wk following the primary challenge, as has been shown by others (40), and that the OVA-specific memory lymphocytes are able to orchestrate the secondary airway inflammatory response upon re-exposure to aerosolized Ag (35).…”

“…1, was modified from the 6-wk discontinuous model characterized by Schramm et al (35). Six-week-old female C57BL/6J mice were immunized with OVA (25 g, grade V; SigmaAldrich) emulsified in CFA containing 250 g of killed Mycobacterium tuberculosis H37 Ra (BD Diagnostic Systems) (s.c.; Th1-type conditions) or adsorbed to 2 mg of Al(OH) 3 (i.p.…”

“…Exposures were 1 h for 7 consecutive days delivered via a nose-only inhalation exposure chamber with space for exposing 48 mice simultaneously (In-Tox Products). In some experiments, 6 -8 wk after the initial aerosol exposure, a time when the inflammatory response had resolved (35), females were bred with naive C57BL/6J males. Pregnant mice were subjected to a secondary challenge with aerosolized OVA daily, at embryonic day (E) 3 E11-17 of pregnancy (day of vaginal plug is E0).…”

“…It has been demonstrated that adult mice subjected to a discontinuous (interrupted) model of OVA-induced allergic airway disease develop secondary allergic airway inflammation with all the hallmarks of the primary disease including airway eosinophilia, OVAspecific Ig production, and airway hyperresponsiveness (35). In this model, adult mice are sensitized with OVA-Al(OH) 3 (three weekly immunizations) and 1 wk later are challenged daily with aerosolized OVA.…”

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

“…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.…”