Allergen-specific subcutaneous immunotherapy in allergic asthma: immunologic mechanisms and improvement

Allergic asthma is a disease characterized by persistent allergen-driven airway inflammation, remodeling, and airway hyperresponsiveness. CD4+ T-cells, especially T-helper type 2 cells, play a critical role in orchestrating the disease process through the release of the cytokines IL-4, IL-5, and IL-13. Allergen-specific immunotherapy (SIT) is currently the only treatment with a long-term effect via modifying the natural course of allergy by interfering with the underlying immunological mechanisms. However, although SIT is effective in allergic rhinitis and insect venom allergy, in allergic asthma it seldom results in complete alleviation of the symptoms. Improvement of SIT is needed to enhance its efficacy in asthmatic patients. Herein, the immunoregulatory mechanisms underlying the beneficial effects of SIT are discussed with the ultimate aim to improve its treatment efficacy.Keywords: allergic asthma; immunotherapy; dendritic cell; regulatory T cells; Th2 lymphocytes; hyperresponsiveness; eosinophilia; IgE; IL-1

Advanced glycation endproducts and their receptor in different body compartments in COPD

© 2016 Hoonhorst et al. Background: Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by chronic airway inflammation and emphysema, and is caused by exposure to noxious particles or gases, e.g. cigarette smoke. Smoking and oxidative stress lead to accelerated formation and accumulation of advanced glycation end products (AGEs), causing local tissue damage either directly or by binding the receptor for AGEs (RAGE). This study assessed the association of AGEs or RAGE in plasma, sputum, bronchial biopsies and skin with COPD and lung function, and their variance between these body compartments. Methods: Healthy smoking and never-smoking controls (n = 191) and COPD patients (n = 97, GOLD stage I-IV) were included. Autofluorescence (SAF) was measured in the skin, AGEs (pentosidine, CML and CEL) and sRAGE in blood and sputum by ELISA, and in bronchial biopsies by immunohistochemistry. eQTL analysis was performed in bronchial biopsies. Results: COPD patients showed higher SAF values and lower plasma sRAGE levels compared to controls and these values associated with decreased lung function (p <0.001; adjusting for relevant covariates). Lower plasma sRAGE levels significantly and independently predicted higher SAF values (p < 0.001). One SNP (rs2071278) was identified within a region of 50 kB flanking the AGER gene, which was associated with the gene and protein expression levels of AGER and another SNP (rs2071278) which was associated with the accumulation of AGEs in the skin. Conclusion: In COPD, AGEs accumulate differentially in body compartments, i.e. they accumulate in the skin, but not in plasma, sputum and bronchial biopsies. The association between lower sRAGE and higher SAF levels supports the hypothesis that the protective mechanism of sRAGE as a decoy-receptor is impaired in COPD

Targeting T cells for asthma

The type 2 T-helper (Th2) lymphocyte can be regarded as an important target cell for the treatment of allergic asthma as it plays a crucial role in the initiation, progression and persistence of disease. Several strategies to target Th2 cells can be envisioned. Drugs that prevent Th2-cells from migrating into the lung tissue, such as antibodies to the chemokine receptor CCR4 and inhibitors of the adhesion molecule VLA-4, are promising for the treatment of asthma. To inhibit Th2-cell activation, novel asthma drugs that act on Th2-selective transciption factors such as GATA3 are being developed. Although initial strategies aimed to block the action of Th2-derived cytokines, the generation of counter-regulatory Th1 lymphocytes and regulatory T cells is currently being explored.</p

Macrophages induce and long-term suppression in a mouse asthma model

Increasing evidence suggests that macrophages (M phi) play a crucial downregulatory role in the initiation and progression of allergic asthma. Recently, the current authors demonstrated that ovalbumin (OVA)-loaded M phi (OVA-M phi) suppress subsequent OVA-induced airway manifestations of asthma and that this effect could be potentiated upon selective activation. In the present study, the authors further delineated the underlying pathway by which M phi exert this immunosuppressive effect. To examine the migration of OVA-M phi, cells were labelled with 5' chloromethylfluorescein diacetate (CMFDA) and were administered (i.v.) into OVA-sensitised BALB/c mice. After 20 h, the relevant organs were dissected and analysed using fluorescent microscopy. Allergen-specificity was investigated by treating OVA-sensitised mice with keyhole limpet haemocyanin (KLH)-M phi activated with immunostimulatory sequence oligodeoxynucleotide (ISS-ODN). By lengthening the period between treatment and challenge to 4 weeks it was examined whether OVA-M phi exerted an immunosuppressive memory response. Strikingly, CMFDA-labelled M phi were not trapped in the lungs, but migrated to the spleen. ISS-ODN-stimulated KLH-M phi failed to suppress OVA-induced airway manifestations of asthma. Moreover, treatment with ISS-ODN-stimulated OVA-M phi was still effective after lengthening the period between treatment and challenge. These data demonstrate that allergen-loaded macrophages can induce an indirect immunosuppressive response that is allergen-specific and long lasting, which are both hallmarks of a memory lymphocyte response

Vß8+ T lymphocytes are essential in the regulation of airway hyperresponsiveness and bronchoalveolar 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

CD28/CTLA4 double deficient mice demonstrate crucial role for B7 co-stimulation in the induction of allergic lower airways disease

Background The existence of a third B7-1/B7-2 receptor was postulated in a recent study using a novel mouse strain lacking both CD28 and CTLA4 (CD28/CTLA4(-/-)).Objective In the present study, it was investigated if T cell co-stimulation via the putative B7-1/B7-2 receptor plays a role in the induction of Th2-mediated asthma manifestations in mice.Methods BALB/c wild-type, CD28/CTLA4(-/-) and B7-1/B7-2(-/-) mice were sensitized and aerosol challenged with ovalbumin (OVA).Results At 24 h after the last aerosol, wild-type mice showed airway hyper-responsiveness in vivo and up-regulated levels of serum OVA-specific IgE compared with the situation shortly before OVA challenge. In addition, eosinophil numbers and IL-5 levels in the broncho-alveolar lavage fluid and Th2 cytokine production by lung cells upon OVA re-stimulation in vitro were observed. In agreement with an earlier study, we failed to induce any of the asthma manifestations in B7-1/B7-2(-/-) mice. Importantly, also CD28/CTLA4(-/-) mice showed no asthma manifestations upon OVA sensitization and challenge.Conclusion These data clearly demonstrate that T cell co-stimulation via the putative B7-1/B7-2 receptor appears to have no role in the induction of Th2-mediated asthma manifestations in this murine model and, conversely, that CD28 signalling is crucial.</p

Apocynin and 1400 W prevents airway hyperresponsiveness during allergic reactions in mice

1 The contribution of reactive nitrogen species to the development of airway hyperresponsiveness in a mouse model of allergic inflammation was investigated by the use of selective inhibitors of nitric oxide and superoxide formation. 2 Sensitized mice, repeatedly challenged with ovalbumin showed a significant (P <0.001, n = 9) increase in airway responsiveness measured using whole body plethysmography. This hyperresponsiveness was accompanied by an influx of eosinophils into the airway lumen and increased levels of ovalbumin-specific serum IgE. 3 Treatment of mice with the iNOS inhibitor 1400 W or the NADPH-oxidase inhibitor apocynin did not significantly alter cellular influx into the airway lumen nor serum ovalbumin specific IgE. In contrast, apocynin as well as 1400 W inhibited ovalbumin-induced airway hyperresponsiveness (P 4 These data suggest that the development of airway hyperresponsiveness during the airway inflammation upon ovalbumin challenge is dependent on the release of both superoxide and nitric oxide and is therefore likely to be dependent on reactive nitrogen species. This mechanism, however, is not reflected by 3-nitrotyrosine formation in the airways