- Title
- Type 2 Innate Lymphoid Cell Dysfunction in Severe Asthma and Response to Treatment with Mepolizumab and Omalizumab
- Creator
- Malik Awan, Bilal
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2022
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Asthma is an immunological disease of the airways characterised by chronic airway inflammation and airway remodelling. A small proportion (5–10%) of patients develop severe asthma where the disease remains poorly controlled; as a result, these patients are at risk of morbidity and mortality. This is partly due to type 2 inflammation orchestrated by group 2 innate lymphoid (ILC2) cells. Following activation by airway epithelial cytokines IL-25, IL-33 and TSLP, ILC2 cells secrete type 2 cytokines of IL-4, IL-5 and IL-13, which cause the hallmark features of asthma, such as IgE synthesis, eosinophilia and airway hyperresponsiveness. This thesis is the first report investigating how ILC2 cells of severe allergic and eosinophilic asthma (SA) patients differ from ILC2 cells of control participants. Moreover, we also demonstrate the effect of biologics, such as mepolizumab and omalizumab, on ILC2 cell physiology. In Chapter 4, I successfully demonstrate that ILC2 cells from SA patients demonstrate higher proliferation capacity, which is related to increased secretion of IL-5, IL-13 and IL-6 compared to ILC2 cells from HC, HAC and MA participants. Further, I also observed that ILC2 cell proliferation and cytokine secretion were under the control of TSLPR signalling that involves intracellular signalling pathways of GATA3, NFATc1, STAT1 and STAT3. In Chapter 5 we demonstrate the effects of treatment with mepolizumab and omalizumab over the course of 6 months on SA patients ILC2 cells. We found that treatment with both mepolizumab and omalizumab improved asthma symptoms, reduced exacerbation frequency and reduced oral corticosteroids and salbutamol use. We also found that ILC2 cells from SA patients treated with mepolizumab demonstrated reduced proliferation capacity and type 2 cytokine secretion, which was related to reduced expressions of TSLPR, GATA3 and NFATc1. Further, patients treated with mepolizumab also demonstrated reduced type 2 inflammation like blood eosinophils and FeNo, indicating that ILC2 cells might play a pivotal role. Treatment with omalizumab had inconsistent effects on ILC2 cells physiology and type 2 inflammation. This body of work identifies a novel signalling mechanism in ILC2 cells of SA patients, which is upregulated. It analyses the effect of mepolizumab and omalizumab on ILC2 cell physiology.
- Subject
- asthma; type 2 innate lymphoid cells; biologics therapy; mepolizumab; omalizumab
- Identifier
- http://hdl.handle.net/1959.13/1512261
- Identifier
- uon:56604
- Rights
- Copyright 2022 Bilal Malik Awan
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 2 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 430 KB | Adobe Acrobat PDF | View Details Download |