Chronic Lymphocytic Leukaemia (CLL) is associated with significant immunosuppression, with infection being the predominant cause of death. The immunosuppression is multifactorial and includes hypogammaglobulinaemia and T cell dysfunction. Expanded populations of effector memory T cells which are oligoclonal are postulated to arise in response to common antigenic stimulation. Increased expression of the inhibitory receptor programmed-death 1 (PD-1) has also been reported on the total CD4+ and CD8+ T cells in patients with CLL. Cytomegalovirus is a ubiquitous herpes virus which contributes to the oligoclonal populations of CD4+ and CD8+ T cells described. In the healthy elderly, CMV is associated with an immune risk phenotype and leads to an earlier death. But the impact of CMV on clinical outcome measures in CLL is unknown. Using 60 CMV class I tetramer and for the first time 15 class II tetramer responses, I have characterised the phenotype and function of CMV-specific T cells in patients with CLL. Interestingly, increased expression of PD-1, was observed on CD4+ but not CD8+ CMV-specific T cells which remained constant over time and was not a result of recent T cell activation. Cytokine production of both CD4+ and CD8+ CMV-specific T cells was shown to be impaired in patients with CLL and PD-1 expression on CMV-specific CD4+ T cells contributed to this. Telomere lengths were also greatly reduced in CMV-specific T cells. I have also used droplet digital PCR to successfully measure latent CMV viral load and found in advanced stage disease an increased CMV viral load was detectable. This most likely arises as a result of the increased immunosuppression and T cell dysfunction observed. Despite these findings, this work reports no evidence that CMV infection impacts on clinical outcomes including time to first treatment or overall survival in two large independent cohorts of patients with CLL.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:693366 |
| Date | January 2016 |
| Creators | Parry, Helen Marie |
| Publisher | University of Birmingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://etheses.bham.ac.uk//id/eprint/6921/ |
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