No abstract

T lymphocytes have a central regulatory role in the pathogenesis of asthma. We delineated the participation of lymphocytes in the acute allergic and chronic tolerant stages of a murine model of asthma by characterizing the various subsets of lymphocytes in bronchoalveolar lavage and lung tissue associated with these responses. Acute (10-day) aerosol challenge of immunized C57BL/6J mice with ovalbumin resulted in airway eosinophilia , histological evidence of peribronchial and perivascular airway inflammation, clusters of B cells and TCR␥␦ cells in lung tissue, increased serum IgE levels , and airway hyperresponsiveness to methacholine. In mice subjected to chronic (6-week) aerosol challenge with ovalbumin, airway inflammation and serum IgE levels were significantly attenuated and airway hyperresponsiveness was absent. The marked increases in lung B and T cell populations seen in the acute stage were also significantly reduced in the chronic stage of this model. Thus , acute ovalbumin challenge resulted in airway sensitization characteristic of asthma, whereas chronic ovalbumin challenge elicited a suppressed or tolerant state. The transition from antigenic sensitization to tolerance was accompanied by shifts in lymphocyte profiles in the lung and bronchoalveolar lavage fluid. Asthma is the most common chronic illness in developed countries. Our current understanding of the pathophysiology of allergic asthma is that it occurs from a breakdown of the normal tolerance to inhaled antigens, as a result of complex interactions between host and environmental factors. Emerging evidence suggests that the development of clinical sensitivity versus normal tolerance to inhaled antigens involves the establishment of a dominant population of CD4 ϩ T lymphocytes that are either classified as Th2-like (sensitization) or Th1-like (tolerance).1 Th2 responses are characterized by secretion of the cytokines interleukin (IL)-4 and IL-13, which induce the production of IgE by B cells, 2-5 and IL-5, which regulates the growth, differentiation, and activation of eosinophils.6 Conversely, Th1 responses are characterized by secretion of IL-2, tumor necrosis factor (TNF)-␤, and interferon (IFN)-␥. IFN-␥ has been shown to stimulate low-level IgG production and to potently inhibit IL-4-mediated IgE responses both in vivo and in vitro.7 The mechanisms that control CD4 ϩ T lymphocyte polarization into either Th1 or Th2 phenotypes are incompletely understood but appear to involve genetic predispositions, local factors such as existing cytokine concentrations and inflammation, and antigenic factors such as the potency, dose, and duration of exposure of the eliciting antigen. In susceptible individuals, antigen sensitization results in specific local and systemic IgE production and airway eosinophilia, which in turn induce the airway inflammation, airway hyperresponsiveness, and reversible airway obstruction characteristic of asthma.The factors influencing antigen sensitization or tolerance can be better studied in mice, given their well defined...

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