A Streptococcus pneumoniae-based immunoregulatory therapy for asthma

Asthma is a chronic inflammatory disease of the airways that affects over 300 million people worldwide. The disease is characterised by episodes of breathlessness, coughing, wheezing and airway hyperresponsiveness (AHR). Asthma results from a dysregulation in immunity that is underpinned by a cohort of effector T cell populations including T helper (Th)1, Th2, Th17 and natural killer T (NKT) cells. These effector T cells produce numerous inflammatory cytokines and chemokines that induce eosinophil influx, mucus hypersecretion and AHR. Antigen presenting cells play key roles in priming these responses. Regulatory T cells (Tregs) are essential for suppression of aberrant immune responses and maintenance of immune homeostasis. Both the number and function of Tregs is impaired in asthmatics, compared to healthy individuals. This reinforces the importance of Tregs in regulating a balanced immune response. Microbial agents have been associated with increased or decreased risk of asthma. Microbial agents that have been associated with decreased asthma risk are under intense investigation for their potential utilisation in therapeutic strategies for asthma. Streptococcus pneumoniae vaccination has been associated with decreased asthma-related hospitalisations in children and the elderly. Furthermore, early mouse studies observed that S. pneumoniae infection attenuated blood eosinophilia during parasitic infection. More recent studies have shown that both live and ethanol killed S. pneumoniae suppress the development of allergic airways disease (AAD) in mice, including eosinophil recruitment to the lungs, Th2 cytokine release, mucus hypersecretion and AHR. Therefore S. pneumoniae has the potential for development into a novel immunotherapy for asthma. To examine this concept we first investigated the capacity of human S. pneumoniae vaccines, which were developed to prevent S. pneumoniae infection, to suppress AAD in mouse models (Chapter 2). In the next study, and in order to determine which components were required for S. pneumoniae-mediated suppression of AAD, S. pneumoniae components were tested for their capacity to suppress AAD (Chapter 3). Two potential S. pneumoniae-based immunotherapies were identified: the conjugate vaccine and the combination of type 3 capsular polysaccharide and pneumolysin (T3P+Ply). These S. pneumoniae immunotherapies suppressed the development of AAD when administered before, during and after sensitisation. Importantly, S. pneumoniae immunotherapy also attenuated established AAD. This demonstrated that S. pneumoniae immunotherapy has potential for therapeutic use in the prevention and/or treatment of asthma. To determine the mechanisms involved in S. pneumoniae-mediated suppression of AAD a number of investigations were performed. Tregs were shown to be induced by S. pneumoniae immunotherapy. Furthermore, anti-CD25 antibody-mediated depletion of Tregs reversed the effect of immunotherapy. Hence, Tregs were required for immunotherapy-mediated suppression of AAD. In the third study, Tregs were shown to be induced in a biphasic manner to suppress immune responses and AAD through a broad range of mechanisms (Chapter 4). Together, these studies have identified potential and novel S. pneumoniae immunotherapies for asthma and determined the mechanism of action that underpins suppression of AAD.