- Title
- Characterising innate immune responses and the role of PD-1 in patients with COPD
- Creator
- See, Hayley Victoria
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2015
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Chronic Obstructive Pulmonary Disease (COPD) affects 7.5% of Australians aged over 40 and is the fifth leading cause of death in Australia. When COPD patients exacerbate, their chest symptoms and breathlessness worsen and pathogens are detected in 60% of patients. COPD patients have an increased density of antiviral CD8+ lymphocytes in the lungs. The numbers of IFN-γ-producing CD8+ lymphocytes are increased in the lungs, but there is a decrease in IFN-γ levels in the peripheral blood. IFN-γ is a key Th1 cytokine triggering upregulation of exhaustion markers, PD-1 and PD-L1. Signalling via this pathway can trigger exhaustion of T cells, leading to effector cell inhibition. We hypothesised that peripheral blood mononucleocytes (PBMCs) from COPD patients would have an altered response to common airway pathogens, and that their immune response would be reduced due to an exhausted cell phenotype. We established an in vitro model of rhinovirus-1B infection, finding the interaction of PBMCs with infected epithelium triggers HLA-DR dependent IFN-α and IFN-γ production, and that this response is impaired in PBMCs from patients with moderate to severe COPD, compared with age-matched healthy adults. Using respiratory pathogens, influenza A/H1N1, S.pneumoniae and non-typeable H.influenzae we confirmed an impaired IFN-α and IFN-γ response in COPD patients. pDCs from exacerbating COPD patients showed upregulation of PD-L1. Further to this, the proportion of effector memory CD8+ T lymphocytes (TEM) was reduced in blood from COPD patients, and this correlated with increased PD-1 expression on CD8+ T lymphocytes. Both TEM PD-1+ and increased numbers of CD8+CD44hi T lymphocytes were negatively correlated with lung function. Our findings suggest that pDCs from patients with COPD have an impaired antigen-presenting capacity and a reduced ability to secrete or elicit interferons. Worse lung function in more severe COPD patients may be driven by activation of lung CD8+ T lymphocytes and PD-1 expression, or these may simply be features of the disease process.
- Subject
- COPD; rhinovirus; PD-1; PBMC
- Identifier
- http://hdl.handle.net/1959.13/1059935
- Identifier
- uon:16713
- Rights
- Copyright 2015 Hayley Victoria See
- Language
- eng
- Full Text
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| View Details Download | ATTACHMENT01 | Abstract | 166 KB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Thesis | 7 MB | Adobe Acrobat PDF | View Details Download |