Amani El-Gammal

Allergen-induced airway responses.

Environmental allergens are an important cause of asthma and can contribute to loss of asthma control and exacerbations. Allergen inhalation challenge has been a useful clinical model to examine the mechanisms of allergen-induced airway responses and inflammation. Allergen bronchoconstrictor responses are the early response, which reaches a maximum within 30 min and resolves by 1–3 h, and late responses, when bronchoconstriction recurs after 3–4 h and reaches a maximum over 6–12 h. Late responses are followed by an increase in airway hyperresponsiveness. These responses occur when IgE on mast cells is cross-linked by an allergen, causing degranulation and the release of histamine, neutral proteases and chemotactic factors, and the production of newly formed mediators, such as cysteinyl leukotrienes and prostaglandin D2. Allergen-induced airway inflammation consists of an increase in airway eosinophils, basophils and, less consistently, neutrophils. These responses are mediated by the trafficking and activation of myeloid dendritic cells into the airways, probably as a result of the release of epithelial cell-derived thymic stromal lymphopoietin, and the release of pro-inflammatory cytokines from type 2 helper T-cells. Allergen inhalation challenge has also been a widely used model to study potential new therapies for asthma and has an excellent negative predictive value for this purpose. Environmental allergens are an important cause of asthma http://ow.ly/NxkGi

Emerging monoclonal antibodies as targeted innovative therapeutic approaches to asthma

Asthma is characterized by discordant responses among cells of the adaptive and innate immune systems. This interplay involves a complex pattern of cytokine‐driven processes resulting in cell migration and recruitment, inflammation, and proliferative states. The significant majority of asthmatic patients respond well to conventional inhaled treatments. However, about 5% of asthmatics have severe refractory asthma and account for 50% of the health expenditure on asthma. Human(ized) monoclonal antibodies (hMabs) targeting inflammatory pathways are promising therapeutic agents in asthma management. The anti‐IgE hMab omalizumab was the first biologic treatment approved for the treatment of allergic asthma. Potential future strategies and targets include interleukin (IL)‐5, IL‐4, and IL‐13, anti‐TSLP, IL‐25, and IL‐33. hMabs targeting IL‐5 have shown great promise in severe refractory asthma with a persisting eosinophilia, and clinical trials with hMabs against IL‐13 and IL4Rα have also shown clinical benefit. Studies of hMabs against other cytokines in severe asthma are under way.

Allergen-induced Increases in Sputum Levels of Group 2 Innate Lymphoid Cells in Subjects with Asthma

Rationale: Group 2 innate lymphoid cells (ILC2), a major source of type 2 cytokines, initiate eosinophilic inflammatory responses in murine models of asthma. Objectives: To investigate the role of ILC2 in allergen‐induced airway eosinophilic responses in subjects with atopy and asthma. Methods: Using a diluent‐controlled allergen challenge crossover study, where all subjects (n = 10) developed allergen‐induced early and late responses, airway eosinophilia, and increased methacholine airway responsiveness, bone marrow, blood, and sputum samples were collected before and after inhalation challenge. Measurements and Main Results: ILC2 (lin−Fc&egr;RI−CD45+CD127+ST2+) and CD4+T lymphocytes were enumerated by flow cytometry, as well as intracellular IL‐5 and IL‐13 expression. Steroid sensitivity of ILC2 and CD4+ T cells was investigated in vitro. A significant increase in total, IL‐5+, IL‐13+, and CRTH2+ ILC2 was found in sputum, 24 hours after allergen, coincident with a significant decrease in blood ILC2. Total, IL‐5+, and IL‐13+, but not CRTH2+, CD4+ T cells significantly increased at 24 and 48 hours after allergen in sputum. In blood and bone marrow, only CD4+ cells demonstrated increased activation after allergen. Airway eosinophilia correlated with IL‐5+ ILC2 at all time points and allergen‐induced changes in IL‐5+ CD4+ cells at 48 hours after allergen. Dexamethasone significantly attenuated IL‐2‐ and IL‐33‐stimulated IL‐5 and IL‐13 production by both cell types. Conclusions: Innate and adaptive immune cells are increased in the airways associated with allergic asthmatic responses. Total and type 2 cytokine‐positive ILC2 are increased only within the airways, whereas CD4+ T lymphocytes demonstrated local and systemic increases. Steroid sensitivity of both cells may explain effectiveness of this therapy in those with mild asthma.

Allergen-induced Changes in Bone Marrow and Airway Dendritic Cells in Subjects with Asthma

RATIONALE Dendritic cells (DCs) are antigen-presenting cells essential for the initiation of T-cell responses. Allergen inhalation increases the number of airway DCs and the release of epithelial-derived cytokines, such as IL-33 and thymic stromal lymphopoietin (TSLP), that activate DCs. OBJECTIVES To examine the effects of inhaled allergen on bone marrow production of DCs and their trafficking into the airways in subjects with allergic asthma, and to examine IL-33 and TSPL receptor expression on DCs. METHODS Bone marrow, peripheral blood, bronchoalveolar lavage (BAL), and bronchial biopsies were obtained before and after inhalation of diluent and allergen from subjects with asthma that develop allergen-induced dual responses. Classical DCs (cDCs) were cultured from bone marrow CD34(+) cells. cDC1s, cDC2s, and plasmacytoid DCs were measured in bone marrow aspirates, peripheral blood, and BAL by flow cytometry, and cDCs were quantified in bronchial biopsies by immunofluorescence staining. MEASUREMENTS AND MAIN RESULTS Inhaled allergen increased the number of cDCs grown from bone marrow progenitors, and cDCs and plasmacytoid DCs in bone marrow aspirates 24 hours after allergen. Allergen also increased the expression of the TSLP receptor, but not the IL-33 receptor, on bone marrow DCs. Finally, inhaled allergen increased the percentage of cDC1s and cDC2s in BAL but only cDC2s in bronchial tissues. CONCLUSIONS Inhaled allergen increases DCs in bone marrow and trafficking of DCs into the airway, which is associated with the development airway inflammation in subjects with allergic asthma. Inhaled allergen challenge also increases expression of TSLP, but not IL-33, receptors on bone marrow DCs.

Glucagon‐like peptide‐1 receptor expression on human eosinophils and its regulation of eosinophil activation

Glucagon‐like peptide‐1 (GLP‐1) and its receptor are part of the incretin family of hormones that regulate glucose metabolism. GLP‐1 also has immune modulatory roles.

Comparison of the Provocative Concentration of Methacholine Causing a 20% Fall in FEV1 between the AeroEclipse II Breath-Actuated Nebulizer and the Wright Nebulizer in Adult Subjects with Asthma

RATIONALE The American Thoracic Society guidelines for methacholine testing for the diagnosis of asthma recommends the 2-minute tidal breathing protocol with the Wright nebulizer, which produces more aerosol than required, generates a small particle size, and requires cleaning between tests. OBJECTIVES To evaluate methacholine testing using a disposable, breath-actuated AeroEclipse II, which produces aerosol during inspiration and was developed for single-patient use. METHODS Forty-six adult subjects with asthma (19 men), aged 27.3 (SD, 9.5) years, with FEV1 98.5 (SD, 18.1) % predicted participated in a randomized, crossover, observational study. Subjects were first screened using the Wright nebulizer, then assigned to 2 minutes of tidal breathing from the Wright or 20 seconds of tidal breathing from the AeroEclipse nebulizer on 2 separate days, in random order. Provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) values were calculated by linear interpolation of log dose-versus-response curves, log-transformed, and compared using paired Student t test and Pearson correlation. MEASUREMENTS AND MAIN RESULTS The 38 subjects demonstrating reproducible PC20 measurements of within 1.5 doubling concentrations were included in the comparison. The geometric mean methacholine PC20 measured with the AeroEclipse nebulizer was approximately 1 doubling concentration lower than the geometric mean methacholine PC20 of the Wright nebulizer (P < 0.05). The Pearson correlation coefficient between the two nebulizers was 0.86 (P < 0.05). CONCLUSIONS The PC20 measurements using the two nebulizers were highly correlated; however, the PC20 determined with the AeroEclipse nebulizer was significantly lower than those determined using the Wright nebulizer. Clinical trial registered with www.clinicaltrials.gov (NCT 01919424).

Anti-IgE and Biologic Approaches for the Treatment of Asthma

Current asthma treatments are effective for the majority of patients with mild-to-moderate disease. However, in those with more severe refractory asthma, agents other than inhaled corticosteroids and beta-agonists are needed both to better manage this group of patients and to avoid the side effects of high-dose corticosteroids and the social and personal hardship endured. Several biological pathways have been targeted over the last 20 years, and this research has resulted in pharmacological approaches to attempt to better treat patients with severe refractory asthma. The flagship of the biologics, the anti-IgE monoclonal antibody, omalizumab, has proven efficacious in selected subgroups of asthma patients. Tailoring asthma treatments to suit specific subtypes of asthma patients is in keeping with ideals of personalized medicine. Research in the complex interplay of allergens, epithelial host defenses, cytokines, and innate and adaptive immunity interactions has allowed better understanding of the mechanics of allergy and inflammation in asthma. As a result, new biologic treatments have been developed that target several different phenotypes and endotypes in asthma. As knowledge of the efficacy of these biological agents in asthma emerges, as well as the type of patients in whom they are most beneficial, the movement toward personalized asthma treatment will follow.