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...

Mice sensitized to ovalbumin (OVA) develop a biphasic response to OVA aerosols, such that acute exposure results in allergic airway disease (AAD) while chronic exposure results in local inhalational tolerance (LIT), with resolution of local pulmonary responses but persistence of the systemic allergic response. We have previously reported that B cell lymphocytosis persists in hilar lymph nodes (HLN) during LIT and that CD4+CD25+Foxp3+ Treg cells are significantly increased in the HLN of LIT mice. This raised the consideration that B cells were involved in modulating the LIT response. Methods and Results: CD19+ B cells isolated from HLN of LIT mice were transferred to sensitized mice before inhaled antigen challenge. Compared to vehicle or AAD CD19+ transferred mice, LIT CD19+ transferred mice developed less BAL leukocytosis and eosinophilia (p < 0.05). In vivo, mice with attenuated AAD following LIT HLN B cell transfer showed a significant increase in the percentages of CD4+ Foxp3+ Treg cells in BAL and HLN, but not systemically (p < 0.03). This protection was antigen specific as LIT HLN B cells did not limit inflammation when transferred to bovine serum albumin (BSA) sensitized mice that were subsequently aerosolized with BSA. In vitro, LIT HLN B cells induced conversion of CD4+CD25‐ Teff cells to CD4+CD25+Foxp3+ T regulatory cells (Treg). The ability to induce suppressive Treg cells was regional, since B cells from AAD or systemic sites during LIT failed to do so. CFSE labeling of LIT HLN B cells demonstrated that these B cells home in and are retained at active sites of inflammation. Conclusions: These observations support a novel mechanism of regional immune regulation, possibly related to the development of a subset of regulatory B cells within the LIT HLN B cell population. This work was funded by NIH/AI R01 HL‐43573

In a biphasic, ovalbumin (OVA)-induced murine asthma model where allergic airway disease is followed by resolution and the development of local inhalational tolerance (LIT), TGFβ-expressing CD5+ B cells were selectively expanded locally in hilar lymph nodes (HLN) of LIT mice. LIT HLN CD5+ B cells but not LIT HLN CD5− B cells induced expression of Foxp3 in CD4+ CD25− T cells in vitro. These CD5+ regulatory B cells and CD4+Foxp3+ T cells demonstrated similar increases in expression of chemokine receptors (CXCR4 and CXCR5) and co-localized in HLN B cell zones of LIT mice. The adoptive transfer of LIT HLN CD5+ B cells, but not LIT HLN CD5− B cells, increased the number of CD4+Foxp3+ T cells in the lung and inhibited airway eosinophilia in this OVA model. Thus, regulatory B cells in HLNs of LIT mice reside in a CD5+ TGFβ-producing subpopulation and co-localize with CD4+Foxp3+ T cells.

Bromelain attenuated development of AAD while altering CD4+ to CD8+ T lymphocyte populations. The reduction in AAD outcomes suggests that bromelain may have similar effects in the treatment of human asthma and hypersensitivity disorders.

Staphylococcus aureus, a primary source of bacterial superantigen (SAg), is known to colonize the human respiratory tract and has been implicated in airway inflammation. Studies have documented a role for SAgs in respiratory disorders, such as nasal polyps, chronic obstructive pulmonary disease, chronic rhinosinusitis, and asthma. However, cellular and molecular mediators involved in SAg-mediated pulmonary disease have not been clearly identified. In this study, we investigated the effect of intranasal staphylococcal enterotoxin A (SEA) exposure on murine lung. The pathological features in the lung resulting from SEA exposure had characteristics of both obstructive and restrictive pulmonary disorders. There was also an increase in bronchoalveolar lavage protein concentration and cellularity following SEA challenge. Massive CD8+Vβ3+ T cell accumulation observed in the lung was dependent on CD4 T cell help, both for recruitment and for IFN-γ synthesis. The primary source of IFN-γ synthesis was CD8 T cells, and depletion of these cells abrogated disease. IFN-γ deficiency also prevented SEA-mediated disease, and this was by enhancing early recruitment of neutrophils as detected in the bronchoalveolar lavage. Thus, IFN-γ appeared to selectively aid the recruitment of T cells to the lungs while preventing the neutrophil accumulation. Therefore, our results show that IFN-γ-producing CD8 T cells mediated pulmonary alveolitis and inflammation, which were dependent upon CD4 T cells for their recruitment to the lung.