The hygiene hypothesis : immunological mechanisms of airway tolerance

The hygiene hypothesis was initially proposed as an explanation for the alarming rise in allergy prevalence in the last century. The immunological idea behind this hypothesis was a lack of infections associated with a Western lifestyle and a consequential reduction in type 1 immune responses. It is now understood that the development of tolerance to allergens depends on microbial colonization and immunostimulatory environmental signals during early-life or passed on by the mother. These environmental cues are sensed and integrated by barrier epithelial cells of the lungs and possibly skin, which in turn instruct dendritic cells to regulate or impede adaptive T cell responses. Recent reports also implicate immunoregulatory macrophages as powerful suppressors of allergy by the microbiome. We propose that loss of adequate microbial stimulation due to a Western lifestyle may result in hypersensitive barrier tissues and the observed rise in type 2 allergic disease

Prophylactic allergen immunotherapy with Der p 2 prevents murine asthma by regulating lung GM-CSF

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Role of NKp46+ natural killer cells in house dust mite-driven asthma

House dust mite (HDM)-allergic asthma is driven by T helper 2 (Th2) lymphocytes, but also innate immune cells control key aspects of the disease. The precise function of innate natural killer (NK) cells during the initiation and propagation of asthma has been very confusing, in part because different, not entirely specific, strategies were used to target these cells. We show that HDM inhalation rapidly led to the accumulation of NK cells in the lung-draining lymph nodes and of activated CD69+ NK cells in the bronchoalveolar lumen. However, genetically engineered Ncr1-DTA or Ncr1-DTR mice that constitutively or temporarily lack NK cells, still developed all key features of acute or chronic HDM-driven asthma, such as bronchial hyperreactivity, Th2 cytokine production, eosinophilia, mucus overproduction, and Th2-dependent immunoglobulin serum titers. The same results were obtained by administration of conventional NK1.1 or asialo-GM1 NK cell-depleting antibodies, antibody-mediated blocking of the NKG2D receptor, or genetic NKG2D deficiency. Thus, although NK cells accumulate in allergen-challenged lungs, our findings comprehensively demonstrate that these cells are not required for HDM-driven asthma in the mouse

Technology-supported sitting balance therapy versus usual care in the chronic stage after stroke : a pilot randomized controlled trial

Background: Technology development for sitting balance therapy and trunk rehabilitation is scarce. Hence, intensive one-to-one therapist-patient training is still required. We have developed a novel rehabilitation prototype, specifically aimed at providing sitting balance therapy. We investigated whether technology-supported sitting balance training was feasible and safe in chronic stroke patients and we determined whether clinical outcomes improved after a four-week programme, compared with usual care. Methods: In this parallel-group, assessor-blinded, randomized controlled pilot trial, we divided first-event chronic stroke participants into two groups. The experimental group received usual care plus additional therapy supported by rehabilitation technology, consisting of 12 sessions of 50 min of therapy over four weeks. The control group received usual care only. We assessed all participants twice pre-intervention and once post-intervention. Feasibility and safety were descriptively analysed. Between-group analysis evaluated the pre-to-post differences in changes in motor and functional outcomes. Results: In total, 30 participants were recruited and 29 completed the trial (experimental group: n = 14; control group: n = 15). There were no between-group differences at baseline. Therapy was evaluated as feasible by participants and therapist. There were no serious adverse events during sitting balance therapy. Changes in clinical outcomes from pre- to post-intervention demonstrated increases in the experimental than in the control group for: sitting balance and trunk function, evaluated by the Trunk Impairment Scale (mean points score (SD) 7.07 (1.69) versus 0.33 (2.35); p < 0.000); maximum gait speed, assessed with the 10 Metre Walk Test (mean gait speed 0.16 (0.16) m/s versus 0.06 (0.06) m/s; p = 0.003); and functional balance, measured using the Berg balance scale (median points score (IQR) 4.5 (5) versus 0 (4); p = 0.014). Conclusions: Technology-supported sitting balance training in persons with chronic stroke is feasible and safe. A four-week, 12-session programme on top of usual care suggests beneficial effects for trunk function, maximum gait speed and functional balance

Murine models of allergic asthma

Allergic asthma is a heterogeneous inflammatory lung disease affecting millions of people worldwide and with a steadily increasing incidence. Mouse models have been of utmost importance in uncovering key inflammatory cell types, cytokines, and pathways in the development and maintenance of allergic asthma. Historically, the mainstay in experimental asthma research was sensitizing rodents to the model protein antigen ovalbumin (OVA) with the pro-Th2 adjuvant aluminum hydroxide, followed by repetitive OVA exposures to the airways to initiate a Th2-skewed adaptive immune response leading to eosinophilic airway inflammation and airway hyperreactivity (AHR). In the last 5 years, OVA is often replaced by naturally occurring allergens such as house dust mite (HDM) or cockroach extracts, but the principle of first sensitizing and then repetitively challenging mice with the same antigen is unchanged. Here, we describe an often used and relevant HDM-based protocol to establish acute allergic asthma, and the methods we have developed to rapidly analyze inflammatory cell infiltration in the bronchalveolar lavage fluid by flow cytometry. Moreover, we explain the methods to restimulate T cells from lung-draining mediastinal lymph nodes with HDM to allow the measurement of cytokine secretion profiles of allergen reactive T cells

Mouse models of asthma

Allergic asthma is a chronic inflammatory disease of the conducting airways characterized by the presence of allergen-specific IgE, Th2 cytokine production, eosinophilic airway inflammation, bronchial hyperreactivity, mucus overproduction, and structural changes in the airways. Investigators have tried to mimic these features of human allergic asthma in murine models. Whereas the surrogate allergen ovalbumin has been extremely valuable for unravelling underlying mechanisms of the disease, murine asthma models depend nowadays on naturally occurring allergens, such as house dust mite (HDM), cockroach, and Alternaria alternata. Here we describe a physiologically relevant model of acute allergic asthma based on sensitization and challenge with HDM extracts, and compare it with the ovalbumin/alum-induced asthma model. Moreover, we propose a detailed readout of the asthma phenotype, determining the degree of eosinophilia in bronchoalveolar lavage fluids by flow cytometry, visualizing goblet cell metaplasia, and measuring Th cytokine production by lung-draining mediastinal lymph node cells restimulated with HD