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Asthma is a chronic disease of the airways, most commonly driven by immuno-inflammatory responses to ubiquitous airborne antigens. Epidemiological studies have shown that disease is initiated early in life when the immune and respiratory systems are functionally immature and less able to maintain homeostasis in the face of continuous antigen challenge. Here, we examine the cellular and molecular mechanisms that underlie initial aeroallergen sensitization and the ensuing regulation of secondary responses to inhaled allergens in the airway mucosa. In particular, we focus on how T-regulatory (Treg) cells influence early asthma initiation and the potential of Treg cells as therapeutic targets for drug development in asthma. [ABSTRACT FROM AUTHOR]

Airway epithelial cells act through multiple mechanisms to function as an important component of the pulmonary defence strategy that is crucial to the maintenance of immune homeostasis. Dendritic cells are uniquely potent inducers of immune responses and it is increasingly clear that epithelium has the capacity to modulate the functional activity of dendritic cells, and vice versa, through production of a diverse array of mediators. Bidirectional interactions between epithelial cells and dendritic cell networks can thus impact upon the development and progression of immunity/tolerance in respiratory tissues. In this brief review we highlight the most recent advances in understanding how airway epithelial/dendritic cell interactions contribute to allergic disorders. [ABSTRACT FROM AUTHOR]

Abstract: Airways hyperresponsiveness (AHR) is one of the major clinical features of allergic airways disease including allergic asthma, however the immunological mechanisms leading to the induction and regulation of this disorder are not fully understood. In this review we will summarise the evidence of a number of studies, principally in murine models of AHR, suggesting a central role for respiratory tract dendritic cells (RTDC) in the induction of AHR through the generation of lung-homing, allergen-specific effector T cells. We will also summarise the evidence supporting a role for regulatory T cells in the attenuation of AHR and will propose that, as a counterpoint to their capacity to induce AHR, RTDC may also play a role in the attenuation of AHR through the generation of regulatory T cells (Treg). A better understanding of the relationship between the physiological and immunological responses to allergen-induced AHR attenuation, and particularly the role of RTDC and Treg in this process, will be essential for the development of new treatments and therapies. [Copyright &y& Elsevier]

• A model of rhinovirus induced exacerbation of cigarette smoke induced lung disease. • HRV-1A infection post cigarette-smoke exposure altered mouse lung structure. • Long-term cigarette smoke exposure and HRV have independent and combined effects. A significant proportion of chronic obstructive pulmonary disease exacerbations are strongly associated with rhinovirus infection (HRV). In this study, we combined long-term cigarette smoke exposure with HRV infection in a mouse model. Our aim was to better understand the effects of HRV infection on such exacerbations, using a realistic method for generating a COPD-like phenotype. After 12-weeks of cigarette smoke exposure, adult female BALB/c mice were infected with HRV-1A and three days later we assessed a range of outcomes including lung volume and function, collected lung tissue for measurement of viral titre, bronchoalveolar lavage for assessment of pulmonary inflammation and levels of key mediators, and fixed lungs for stereological structural analyses. Cigarette smoke exposure alone significantly increased total cells and macrophages, and reduced MIP-2 in bronchoalveolar lavage. HRV-1A infection alone increased neutrophilic inflammation, IP-10 and total protein in lavage and also increased specific airway resistance measured at functional residual capacity. Cigarette smoke and HRV-1A together impacted various lung structural parameters including increasing stereological lung volume. Our results show that long-term cigarette smoke exposure and HRV-1A infection both individually impact respiratory outcomes and combine to alter aspects of lung structure in a mouse model, thus providing insight into the development of future mechanistic studies and appropriate interventions in human disease. [ABSTRACT FROM AUTHOR]

Abstract: Scarring after severe burn is a result of changes in collagen deposition and fibroblast activity that result in repaired but not regenerated tissue. Re-epithelialisation of wounds and dermal cell repopulation has been thought to be driven by cells in the periphery of the wound. However, recent research demonstrated that cells originating from the bone marrow contribute to healing wounds in other tissues and also after incisional injury. We investigated the contribution of bone marrow-derived cells to long-term cell populations in scar tissue (primarily fibroblasts and keratinocytes) after severe burn. Wild-type mice were lethally irradiated and then the bone marrow reconstituted by injection of chimeric bone marrow cells expressing EGFP marker protein. Mice with chimeric bone marrow were then given a burn, either an 1-cm diameter injury (to mimic minor injury) or 2-cm diameter (to mimic moderate injury). Wounds were analysed at days 1, 3, 7, 14, 21, 28, 56 and 120 using FACS and immunohistochemistry to identify the percentage and cell type within the wound originating from the bone marrow. The inflammatory cell infiltrate at the early time-points was bone marrow in origin. At later time-points, we noted that over half of the fibroblast population was bone marrow-derived; we also observed that a small percentage of keratinocytes appeared to be bone marrow in origin. These findings support the theory that the bone marrow plays an important role in providing cells not only for inflammation but also dermal and epidermal cells during burn wound healing. This increases our understanding of cell origins in the healing wound, and has the potential to impact on clinical practice providing a potential mechanism for intervention away from conventional topical treatments and directed instead to systemic treatments affecting the bone marrow response. [Copyright &y& Elsevier]

Dendritic cells (DCs) play a central role in regulating innate and adaptive immune responses. It is well accepted that their regulatory functions change over the life course. In order to study DCs function during early life it is important to characterize the function of neonatal DCs. However, the availability of neonatal DCs is limited due to ethical reasons or relative small samples of cord blood making it difficult to perform large-scale experiments. Our aim was to establish a robust protocol for the generation of neonatal DCs from cord blood derived CD34+ hematopoietic stem cells. For the expansion of DC precursor cells we used a cytokine cocktail containing Flt-3 L, SCF, TPO, IL-3 and IL-6. The presence of IL-3 and IL-6 in the first 2 weeks of expansion culture was essential for the proliferation of DC precursor cells expressing CD14. After 4 weeks in culture, CD14+ precursor cells were selected and functional DCs were generated in the presence of GM-CSF and IL-4. Neonatal DCs were then stimulated with Poly(I:C) and LPS to mimic viral or bacterial infections, respectively. Poly(I:C) induced a higher expression of the maturation markers CD80, CD86 and CD40 compared to LPS. In line with literature data using cord blood DCs, our Poly(I:C) matured neonatal DCs cells showed a higher release of IL-12p70 compared to LPS matured neonatal DCs. Additionally, we demonstrated a higher release of IFN-γ, TNF-α, IL-1β and IL-6, but lower release of IL-10 in Poly(I:C) matured compared to LPS matured neonatal DCs derived from cord blood CD34+ hematopoietic stem cells. In summary, we established a robust protocol for the generation of large numbers of functional neonatal DCs. In line with previous studies, we showed that neonatal DCs generated form CD34+ cord blood progenitors have a higher inflammatory potential when exposed to viral than bacterial related stimuli. • A robust protocol for the generation of high numbers of neonatal dendritic cells. • IL-3 and IL-6 are crucial for the proliferation of cord blood CD34+ progenitors. • Neonatal DCs have a higher inflammatory potential when exposed to viral stimuli. • LPS induces higher release of IL-10 in neonatal DCs compared to Poly(I:C). [ABSTRACT FROM AUTHOR]