Jürgen Schwarze's group studies immune mechanisms of viral bronchiolitis and the role of virus induced immune modulation in allergy and asthma focusing on the innate/adaptive immune interface in the lung.
Infection with human respiratory syncytial virus (RSV) is the leading cause of viral bronchiolitis in infants and young children, accounting for ~70% of cases. RSV-bronchiolitis is associated with intense inflammation of the terminal airways and impairment of lung function, resulting in severe disease that requires hospital admission in about 2% of all infants. Globally, it is estimated that RSV is responsible for 64 million cases every year, resulting in 160,000 deaths. In addition, in the elderly, RSV results in considerable morbidity and mortality, similar to non-pandemic influenza. Furthermore, RSV bronchiolitis in infants is associated with an increased risk of subsequent recurrent wheeze, childhood asthma, and early sensitisation to allergens. Thus, RSV infections constitute a major health and economic burden. Despite this there is neither a vaccine available nor do we have any specific treatment for RSV-bronchiolitis that would shorten the disease or reduce its severity.
Driven by the lack of disease modifying therapy for severe RSV disease and inspired by findings of an increased risk of asthma development and allergic sensitisation following RSV bronchiolitis in infants, my research since 1994 has focused on understanding virus-induced immune-modulation and inflammation in the lung.
Dendritic cells as professional antigen presenting cells are essential for antigen-specific activation of T-cells and determine the quality of T-cell responses. In healthy lungs mature dendritic cells are rare and the immune environment is tolerogenic. Following RSV infection, we have demonstrated marked increases in numbers of mature pulmonary dendritic cells with increased antigen-presenting capacity. These increases occur with the advent of virus induced inflammation, when antiviral immune responses have already been triggered, and are still evident when the infection has resolved. Using both pre-clinical models and clinical samples, we currently investigate the role of these mature lung dendritic cells for the course of RSV induced inflammation and lung function changes, as well as for subsequent immune responses. Characterising subsets of myeloid and plasmacytoid dendritic cells in the lung by analysing their co-stimulatory molecules, cytokines and function, we aim to determine if virus induced lung dendritic cells are involved in modulating pulmonary immune responses and to elucidate their role in maintenance or resolution of RSV induced inflammation, in the development of T-cell memory to RSV antigens and in enhanced responses to allergens following RSV infection.
We have recently found that, in analogy to gut epithelial cells, lung epithelial cells can completely inhibit antigen-specific T cell proliferation and that this inhibition is lost when epithelial cells are infected with RSV. Currently, we work to understand the inhibitory mechanisms involved and the effects of viral infection on these. In a collaboration with Professor Antoon van Osterhout (University of Groningen, NL) we seek to determine if the inhibitory capacity of lung epithelial cells is altered in patients with asthma.
There is no effective treatment that would shorten or reduce the intensity of severe RSV disease. Helminth infections can potently inhibit allergic airways inflammation in pre-clinical models. We therefore investigate in a pre-clinical model, in collaboration with Professor Rick Maizels, if and how helmiths or their products can mitigate disease and pulmonary inflammation associated with RSV infection. In addition, we collaborate with Dr Donald Davidson to study the ability of anti-microbial peptides to reduce RSV infection and subsequent disease.
Investigating the origin of mature DCs after RSV infection we have recently found that they are primarily derived from local precursors in the lung, which are depleted in the process, resulting in a prolonged inability to mount a normal DCs response to a secondary stimulus. This may have major implications for the defence against secondary respiratory infections in particular with bacteria. Studies investigating the role of lung DCs in the interaction between concomitant and serial infections are currently being developed.
The role of viral persistence in immune-modulation and development of reactive airway disease.
Genetically modified dendritic cells as tool for therapeutic immune-modulation and vaccination in allergy and respiratory viral infections.
Mechanisms of peptide immunotherapy in allergic airways disease (collaboration with Professor Steve Anderton) and the influence of respiratory viral infections on induction and maintenance of tolerance.
Professor Schwarze (FRCPCH) is the Edward Clark Chair of Child Life and Health at the University of Edinburgh, a paediatrician specialised in allergist and respiratory medicine, and an internationally recognised expert in immune mechanisms of RSV bronchiolitis and associated airway allergy.
Dr Schwarze qualified in Medicine from Freiburg University, Germany in 1988, trained as a paediatrician specialising in paediatric respiratory medicine and paediatric allergy and he now leads the paediatric allergy service at the Royal Hospital for Sick Children Edinburgh and is the clinical lead for the national Children's and Young People's Allergy Network Scotland.
In 1994, as a post-doctoral fellow at National Jewish Medical and Research Centre in Denver, Colorado, Dr Schwarze started to work on immune responses in RSV bronchiolitis and allergic airway disease. He continued his research at the Ruhr-University Bochum, Germany, and from 2002 to 2007 at Imperial College London where, as a Wellcome Trust Senior Fellow, he focused his research on the role of lung dendritic cells in respiratory viral infections and subsequent reactive airway disease. In 2007 he moved to the MRC Centre for Inflammation Research at the University of Edinburgh and took up his current Chair in 2008.
Professor Schwarze's research programme aims to understand mechanisms of inflammation at the interface of innate and adaptive immunity in respiratory viral infections to help develop urgently required treatments for viral bronchiolitis in infants and virus driven asthma exacerbations. He uses both pre-clinical models and clinical samples to investigate the roles of lung dendritic cells and airway epithelial cells in the induction, maintenance and resolution of virus induced immune responses and inflammation in the lung. A second focus of his work are studies to understand mechanisms of immune tolerance to allergens using models of peptide immunotherapy.