- Title
- Immunoregulatory therapies for inflammatory diseases
- Creator
- Monogar, Prema Mono Nair
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2016
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD) and influenza affect millions of people worldwide. The lack of effective therapies for these diseases means there is an urgent need to understand the immune mechanisms underpinning these diseases in order to develop more effective therapies. Asthma is a chronic inflammatory disease of the airways characterised by recurring symptoms of wheezing, coughing and chest tightness. The development and progression of asthma is primarily due to the actions of activated mast cells, eosinophils and type 2 helper (Th2) lymphocytes upon exposure to allergens. These cells release mediators that result in inflammation, oedema and mucus hypersecretion, which are often accompanied by airway hyper-responsiveness (AHR). These features collectively lead to narrowing of the airways and airflow obstruction. Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterised by chronic bronchitis, emphysema and airflow limitation, which is not fully reversible. Active smoking of tobacco products remains the most important risk factor for COPD. Recruitment of inflammatory cells and mediators as a result of cigarette smoking leads to oxidative stress and a disruption in the balance between proteases and anti-proteases. Collectively this leads to parenchymal destruction, airway remodelling, narrowing of the airways and ultimately airflow limitation. Influenza is one of the most important respiratory viral infectious diseases in the world. The virus causes annual epidemics and regular pandemics. Frequent genetic mutation of influenza viruses limits the efficacy of current vaccines and antiviral drugs. The common theme and aim of my PhD was to investigate the role of novel immune pathways and factors that may underpin the development of asthma, COPD and control the severity of influenza virus infection. The first study demonstrates a novel role for RelB expression in dendritic cells (DCs) in the development of allergic airway inflammation (AAI). Genetic deletion of RelB led to increased inflammatory cell influx, chemokine and Th2-associated cytokines in the lungs, and airway remodelling that is independent of allergen exposure. Adoptive transfer of RelB-sufficient DCs ameliorated AAI. The second study investigated the benefits of targeting protein phosphatase 2A (PP2A) and the ubiquitin proteasome system (UPS) using immunomodulatory drugs in allergic airway disease (AAD). Enhancing PP2A activity with 2-amino-4-(4-heptyloyphenol)-2-methylbutanol (AAL(S)) is more efficient at suppressing hallmark features of AAD compared to fingolimod (FTY720), while inhibiting proteasome activity with bortezomib (BORT) suppresses certain features of AAD. Our study also demonstrates for the first time that enhancing PP2A and inhibiting proteasome activity at the same time has synergistic effects, and is able to suppress more features of AAD than either AAL(S) or BORT treatment alone. The third study investigated the novel role of the anti-inflammatory molecule, tristetraprolin (TTP), in an experimental model of cigarette smoke (CS)-induced COPD. Our study identified a novel role for TTP in the pathogenesis of experimental COPD. We demonstrate that active TTP is able to reduce the severity of experimental COPD by suppressing CS-induced pulmonary inflammation, pro-inflammatory cytokine and chemokine expression, airway remodelling and lung function impairment. The fourth study furthered our investigation into the role of TTP by investigating the importance of active TTP in a mouse model of influenza virus infection. We demonstrate for the first time that active TTP reduced the severity of infection by enhancing protective antiviral responses, decreasing pro-inflammatory cytokine and chemokine production, and suppressing phosphoinositide 3-kinase (PI3K) activity. Collectively these studies have identified potential novel pathways and molecules that are implicated in asthma, COPD and influenza virus infection. Importantly, these studies have expanded our understanding of disease pathogenesis and demonstrate that therapeutically targeting these pathways and molecules may be novel therapeutic avenues for these respiratory diseases.
- Subject
- asthma; COPD; influenza; RelB; PP2A; ubiquitin proteasome system; tristetraprolin
- Identifier
- http://hdl.handle.net/1959.13/1318457
- Identifier
- uon:23627
- Rights
- Copyright 2016 Prema Mono Nair Monogar
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 7 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 907 KB | Adobe Acrobat PDF | View Details Download |