C von Garnier

Restricted Aeroallergen Access to Airway Mucosal Dendritic Cells In Vivo Limits Allergen-Specific CD4+ T Cell Proliferation during the Induction of Inhalation Tolerance

Chronic innocuous aeroallergen exposure attenuates CD4+ T cell-mediated airways hyperresponsiveness in mice; however, the mechanism(s) remain unclear. We examined the role of airway mucosal dendritic cell (AMDC) subsets in this process using a multi-OVA aerosol-induced tolerance model in sensitized BALB/c mice. Aeroallergen capture by both CD11blo and CD11bhi AMDC and the delivery of OVA to airway draining lymph nodes by CD8α− migratory dendritic cells (DC) were decreased in vivo (but not in vitro) when compared with sensitized but nontolerant mice. This was functionally significant, because in vivo proliferation of OVA-specific CD4+ T cells was suppressed in airway draining lymph nodes of tolerized mice and could be restored by intranasal transfer of OVA-pulsed and activated exogenous DC, indicating a deficiency in Ag presentation by endogenous DC arriving from the airway mucosa. Bone marrow-derived DC Ag-presenting function was suppressed in multi-OVA tolerized mice, and allergen availability to airway APC populations was limited after multi-OVA exposure, as indicated by reduced OVA and dextran uptake by airway interstitial macrophages, with diffusion rather than localization of OVA across the airway mucosal surface. These data indicate that inhalation tolerance limits aeroallergen capture by AMDC subsets through a mechanism of bone marrow suppression of DC precursor function coupled with reduced Ag availability in vivo at the airway mucosa, resulting in limited Ag delivery to lymph nodes and hypoproliferation of allergen-specific CD4+ T cells.

Update in clinical allergy and immunology

In the recent years, a tremendous body of studies has addressed a broad variety of distinct topics in clinical allergy and immunology. In this update, we discuss selected recent data that provide clinically and pathogenetically relevant insights or identify potential novel targets and strategies for therapy. The role of the microbiome in shaping allergic immune responses and molecular, as well as cellular mechanisms of disease, is discussed separately and in the context of atopic dermatitis, as an allergic model disease. Besides summarizing novel evidence, this update highlights current areas of uncertainties and debates that, as we hope, shall stimulate scientific discussions and research activities in the field.

Comment on "Pre- and intra-operative mediastinal staging in non-small-cell lung cancer".

In response to the review published by Lardinois in the Journal [1], we would like to attract both the author’s and readers’ attention to a recent well-conducted European randomised controlled multicentre trial for staging in patients with suspected non-small cell lung cancer (NSCLC) [2]. In this trial, Annema et al. randomised patients with resectable NSCLC and indication for mediastinal staging based on PET-CT to either direct surgical staging, or endosonography (combined endobronchial and oesophageal ultrasound-guided needle aspiration (EBUS-TBNA and EUS-FNA)) followed by surgical staging, when no lymph node metastases were detected. This trial convincingly demonstrated that an approach combining sequential endosonographic and surgical staging significantly improved sensitivity (surgical 79% versus endosonographic 85% versus endosonographic plus surgical 94%) and reduced unnecessary thoracotomies, without causing additional complications. Importantly, endosonographic staging was associated with a six-fold lower complication rate (1% versus 6% for mediastinoscopy). Moreover, an increasing body of literature showed that for experienced operators EBUS and EUS reaches almost all mediastinal lymph node stations with a reported overall sensitivity of 93% [3]. Endosonographic staging is performed as an outpatient procedure with sedation (obviating the need for general anaesthesia), reduces the need for surgical staging in up to twothirds of patients, and is cost-effective [4–7]. Fine needle aspiration tissue samples obtained under endosonography can be prepared as cell blocks that are suitable for molecular analysis [8]. Based on accumulating evidence, we suggest that it is judicious in experienced centres to adopt a staging strategy for NSCLC with sequential endosonography and complementary surgical staging as required, in order to enhance sensitivity for the detection of lymph node metastasis and avoid unnecessary surgical procedures.