Francesca Scordamaglia

Melanoma-associated fibroblasts modulate NK cell phenotype and antitumor cytotoxicity

Although the role of the tumor microenvironment in the process of cancer progression has been extensively investigated, the contribution of different stromal components to tumor growth and/or evasion from immune surveillance is still only partially defined. In this study we analyzed fibroblasts derived from metastatic melanomas and provide evidence for their strong immunosuppressive activity. In coculture experiments, melanoma-derived fibroblasts sharply interfered with NK cell functions including cytotoxicity and cytokine production. Thus, both the IL-2-induced up-regulation of the surface expression of NKp44, NKp30, and DNAM-1 triggering receptors and the acquisition of cytolytic granules were inhibited in NK cells. This resulted in an impairment of the NK cell-mediated killing of melanoma target cells. Transwell cocultures and the use of specific inhibitors suggested that cell-to-cell contact was required for inducing DNAM-1 modulation. In contrast, modulation of NKp44 and NKp30 was due to PGE2 released by fibroblasts during coculture. Normal skin fibroblasts could also partially affect NK cell phenotype and function. However, the inhibitory effect of tumor-derived fibroblasts was far stronger and directly correlated with their ability to produce PGE2 either constitutively or upon induction by NK cells.

New insights into airway remodelling in asthma and its possible modulation.

Purpose of reviewAirway remodelling, a central feature of asthma, is characterized by an alteration in the size, mass or number of tissue components which occur in and around the trachea, bronchi and bronchioles in the airways in response to injury and/or inflammation.The present review focuses on the most recent literature on airway remodelling and on the different drugs commonly used or potentially useful in the treatment of asthma with a particular attention to the studies conducted by our group in the last few years. Recent findingsThe interaction between the epithelium and mesenchymal elements such as fibroblasts is essential for normal airway repair. An abnormal response of this epithelial–mesenchymal trophic unit has been proposed to be central to the airway pathology and physiology characteristic of asthma. Current treatments may indirectly control airway remodelling through a reduction of inflammation but such a kind of approach is only in part successful. SummaryThe clear understanding of the events that take place during remodeling and the targeting of its specific components will be helpful in the development of novel therapies that might restore lung function.

Anti-proliferative and anti-remodelling effect of beclomethasone dipropionate, formoterol and salbutamol alone or in combination in primary human bronchial fibroblasts.

Background:  Bronchial asthma is characterized by lower airway inflammation and remodelling. Anti‐inflammatory treatment with inhaled corticosteroids (ICS) provides the mainstay of asthma therapy together with bronchodilation induced by short‐ and long‐acting inhaled β2‐agonists. Lower airway fibroblasts may play a critical role in airway inflammation and remodelling, suggesting that they might represent an important target for the major anti‐asthmatic drugs. The aim of our study was to investigate the effects of beclomethasone dipropionate (BDP), salbutamol and formoterol either alone or in combination on in vitro cultures of human bronchial fibroblasts.

GPR56 as a novel marker identifying the CD56dull CD16+ NK cell subset both in blood stream and in inflamed peripheral tissues.

To define novel human NK cell markers, we generated two mAbs specific for G-protein-coupled receptor 56 (GPR56), a surface glycoprotein that appears to be involved in cell-to-cell and cell-to-matrix interactions. GPR56 has been described in selected normal tissues, and in certain tumors, while, as yet, its expression on leukocytes is unknown. In this study, we show that anti-GPR56 mAbs, among leukocytes, prevalently recognize NK cells. In particular, these mAbs brightly stain CD56(dull) CD16(+) NK cells while react poorly with CD56(bright) CD16(+/-) NK cells. Consistently, we found that GPR56 was expressed on NK cells populating inflamed peripheral tissues while it was absent in lymph node-derived NK cells. We also show that activating stimuli, such as cytokines or exposure to monocyte-derived dendritic cell, down-regulate NK cell expression of GPR56 both at the protein and at the transcriptional level. Interestingly, IL-18, known to induce de novo expression of CCR7 on CD56(dull) CD16(+) NK cells, displayed the highest capability of modulating GPR56. Thus, together with the identification of GPR56 as a novel marker capable of discriminating different NK cells subsets, our data suggest that GPR56 may take part to the mechanisms regulating NK cell migration through the blood stream, peripheral tissues and lymph nodes.

Levocetirizine in the treatment of allergic diseases

Background: Levocetirizine, the R-enantiomer of cetirizine dihydrochloride, is a new molecule with a potent and selective antihistamine activity. Objective: To investigate the evidence that levocetirizine is an effective therapy for allergic disease. Methods: Evaluation of published articles in English, or having an English abstract. Results: Clinical trials indicate that levocetirizine is safe and effective for the treatment of allergic rhinitis and chronic idiopathic urticaria. The compound shows a rapid onset of action, high bioavailability and affinity for the H1 receptor. Moreover, this molecule demonstrates many anti-inflammatory effects that enhance the clinical therapeutic benefit not only in short-term but also in long-term treatments, as reported in recent trials utilizing levocetirizine for several months. Conclusion: Levocetirizine confirms its safe effective activity for treatment of allergic disease in both adults and children.