V-beta-8+ T lymphocytes are essential in the regulation of airway hyperresponsiveness and bronchial eosinophilia but not in allergen-specific IgE in a murine model of allergic asthma

Background There is increasing evidence that in allergic asthma the inflammatory process is regulated by T lymphocytes. In BALB/c mice the majority of ovalbumin responsive T lymphocytes express the V8.1 and V8.2 T-cell receptor. Objective We analysed the contribution of V8 T lymphocytes during the sensitization and challenge phase in the regulation of antigen-specific IgE, airway hyperresponsiveness and cellular infiltration in the airways in a murine model of allergic asthma. Methods Mice strains genetically lacking (SJL/J and SJA/9) and expressing (BALB/c) the V8 T cell receptor were used. In addition, prior to the sensitization and prior to the challenge BALB/c mice were treated with antibodies to V8. Mice were sensitized with ovalbumin, followed by repeated challenge with ovalbumin or saline aerosols. Results In ovalbumin challenged BALB/c mice treated with control antibody a significant increase in eosinophils in the bronchoalveolar lavage, airway hyperresponsiveness and increased serum levels of ovalbumin-specific IgE were observed compared to control mice. Treatment of BALB/c mice with antibodies to V8 prior to the sensitization or prior to the challenge period completely inhibited the ovalbumin induced infiltration of eosinophils and airway hyperresponsiveness, while ovalbumin-specific IgE was slightly decreased. In SJA/9 and SJL/J mice ovalbumin challenge did not induce eosinophilic infiltration and airway hyperresponsiveness. In SJL/J mice ovalbumin challenge induced an upregulation of ovalbumin-specific IgE, however, in SJA/9 mice no upregulation was observed. Conclusion It is demonstrated that V8 T lymphocytes are essential for infiltration of eosinophils in the airways and development of airway hyperresponsiveness in a murine model of allergic asthma. In contrast, although V8 T lymphocytes seem to be important for the extent of IgE levels, no essential role for V8 T lymphocytes in the induction of antigen-specific IgE was observe

Allergen immunotherapy inhibits airway eosinophilia and hyperresponsiveness associated with decreased IL-4 production by lymphocytes in a murine model of allergic asthma

In the present study, we investigated whether allergen immunotherapy is effective in a murine model with immunologic and pathophysiologic features reminiscent of allergic asthma. Ovalbumin-sensitized mice received increasing (1 ?g to 1 mg) subcutaneous doses of ovalbumin twice a week for 8 wk according to a semirush immunotherapy protocol as used in allergic patients. During immunotherapy, an initial rise in serum levels of ovalbumin-specific antibodies (immunoglobulin [Ig]G1, IgE, IgG2a) occurred, after which IgE levels decreased sharply concomitant with an increase in IgG2a levels. The increase in IgG2a levels, with the decline in IgE levels, suggests that during immunotherapy interferon- production is increased or interleukin (IL)-4 production is decreased. After immunotherapy, inhalation challenge of the mice with ovalbumin revealed almost complete inhibition (98 percent, P < 0.01) of eosinophil infiltration into bronchoalveolar lavage and airway hyperresponsiveness (100 percent at 320 ?g/kg methacholine, P < 0.05) compared with sham-treated animals. In addition, IL-4 production of thoracic lymph node cells stimulated with ovalbumin in vitro was largely reduced (60 percent, P < 0.05) after immunotherapy. Thus, effective immunotherapy in this animal model appears to be due to modulation of antigen-specific T cells. Similar effects on airway symptoms and IL-4 production can be obtained within 1 wk by three injections of the highest dose of ovalbumin (1 mg). This animal model will be used as a preclinical model to improve allergen immunotherapy and to gain more insight into the mechanisms involve

Bronchoconstriction and airway hyperresponsiveness after ovalbumin inhalation in sensitized mice

To investigate the mechanisms underlying airway hyperresponsiveness a murine model was developed with several important characteristics of human allergic asthma. Mice were intraperitoneally sensitized with ovalbumin and after 4 weeks challenge via an ovalbumin aerosol. After aerosol, lung function was evaluated with a non-invasive forced oscillation technique. The amount of mucosal exudation into the airway lumen and the presence of mast cell degranulation was determined. Tracheal responsiveness was measured at several time points after challenge. At these time points also bronchoalveolar lavage and histology were performed. Sensitization induced high antigen-specific IgE levels in serum. Inhalation of ovalbumin in sensitized mice induced an immediate but no late bronchoconstrictive response. During this immediate phase, respiratory resistance was increased (54%). Within the first hour after ovalbumin inhalation increased mucosal exudation and mast cell degranulation were observed. At 12 and 24 h after ovalbumin challenge, mice showed tracheal hyperresponsiveness (29% and 34%, respectively). However, no apparent inflammation was found in the lungs or bronchoalveolar lavage. From these results it can be concluded that hyperresponsiveness can develop via mechanisms independent of an inflammatory infiltrate. Since mast cell degranulation occurred after ovalbumin exposure, we hypothesize that mast cells are involved in the induction of airway hyperresponsiveness in this model

Inhibitory effects of endogenous and exogenous interferon-γ on bronchial hyperresponsiveness, allergic inflammation and T-helper 2 cytokines in Brown–Norway rats

Interferon-γ (IFN-γ) is an important cytokine involved in the regulation of allergen-induced immune responses. We examined the role of IFN-γ in a Brown–Norway rat model of bronchial hyperresponsiveness (BHR) and airway eosinophilia, and its effects on the mRNA expression of T helper type 1 (Th1)/Th2 cytokine. Ovalbumin (OA)-sensitized animals were given either exogenous IFN-γ (105 U/rat over 3 days, intraperitoneally) or anti-IFN-γ blocking antibody (DB-1 0·3 mg/rat, intravenously) prior to exposure to OA aerosol and were studied 18–24 hr later. In sensitized animals, OA induced significant BHR, accumulation of eosinophils, T lymphocytes and neutrophils in bronchoalveolar lavage (BAL) fluid, and also increased eosinophils and CD8+ T cells in the airways. Exogenous IFN-γ attenuated allergen-induced BHR (P<0·02, compared with sham-treated animals) together with a significant reduction in eosinophil and neutrophil numbers in BAL fluid (P<0·005), and eosinophils and CD8+ T cells in airways (P<0·05). By contrast, anti-IFN-γ antibody increased airway CD4+ T cells and BHR. Using reverse transcriptase–polymerase chain reaction, significant increases in Th2 [interleukin-4 (IL-4), IL-5 and IL-10], and IFN-γ cytokine mRNA were found in the lungs of sensitized and OA-exposed animals, while exogenous IFN-γ significantly suppressed IL-4, IL-5 and IL-10 mRNA expression, and anti-IFN-γ antibody increased IL-4 and IL-5 mRNA expression. These results indicate that Th1 effects, such as those mediated by IFN-γ, play a down-regulatory role to suppress the Th2 responses associated with allergen-induced BHR and eosinophilic inflammation

Children living with HIV in Europe: do migrants have worse treatment outcomes?

International audienceTo assess the effect of migrant status on treatment outcomes among children living with HIV in Europe