Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) is a chronic necrosis of the jawbone that occurs in ≈1-5% of patients receiving bisphosphonate medication for conditions such as osteoporosis and certain cancers. Although the pathogenesis of BRONJ is still uncertain, several recent theories have emerged; these include vascular disruption of the jaw tissue; inappropriate osteoclast activation; and direct cytotoxicity of jaw epithelium. However, despite bisphosphonates having well-documented stimulatory effects on immune cells, and BRONJ being associated with oral microbial infections, an immune-mediated pathology for BRONJ has largely been ignored. Bisphosphonates activate human γδ T cells, specifically those that use T cell receptor (TCR) γ-chain variable-region-9, and TCR δ-chain variable-region-2 (Vγ9Vδ2 T cells). These unconventional T cells typically account for ≈ 1-5% of circulating lymphocytes, make protective responses to microbial challenge, and are promising candidates for cancer immunotherapy. In the context of BRONJ, we have hypothesised that bisphosphonate-mediated activation of jaw-associated Vγ9Vδ2 T cells, in the presence of oral microbiota, may drive the disruption of bone turnover that is central to the disease process. On initiation of these studies, it quickly became apparent that traditional characterisation of Vγ9Vδ2 T cells using CD27/CD45RA was demonstrably sub-optimal, while phenotypic analysis of 63 healthy volunteers revealed an unexpected and surprising degree of Vγ9Vδ2 T cell heterogeneity; both of which are likely to confuse assessment of disease scenarios. Thus, this thesis describes the novel phenotypic and functional characterisation of Vγ9Vδ2 T cells using alternative surface markers and methods of analysis. This reveals that different sets of individuals have different Vγ9Vδ2 T cell “profiles” that predict very different functional capabilities and responses to immunotherapeutic interventions. Using this improved definition of Vγ9Vδ2 T cells, this thesis then describes preliminary investigations of Vγ9Vδ2 T cell development in the human neonatal thymus, and assesses the involvement of Vγ9Vδ22 T cells in a small cohort of eight BRONJ patients.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:667357 |
| Date | January 2014 |
| Creators | Ryan, Paul Leo |
| Publisher | Queen Mary, University of London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://qmro.qmul.ac.uk/xmlui/handle/123456789/9006 |
Page generated in 0.0041 seconds