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Title: Biological and clinical significance of chronic herpes virus infection in patients undergoing treatment for myeloid malignancies
Author: Lewis, David John
ISNI:       0000 0004 5361 1905
Awarding Body: University of Birmingham
Current Institution: University of Birmingham
Date of Award: 2015
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Cytomegalovirus (CMV) is a β-herpes virus that infects the majority of the world’s population. Tyrosine kinase inhibitors (in particular imatinib, dasatinib and nilotinib) have been successfully used in the treatment of chronic myeloid leukaemia, as they target the \(Abl\) kinase, which is constitutively activated in the disease. Although thought of as targeted therapies, they have significant “off target” effects including inhibition of \(Src\) family kinases important in T cell receptor mediated activation. I demonstrated that CMV infection is associated with significant alterations in the immune repertoire in imatinib-treated patients; in particular with expansions of differentiated CD8 T cells and Vδ1 γδ T cells. Furthermore, dasatinib treatment is associated with evidence of subclinical CMV reactivation and marked expansions of terminally differentiated CD8 T cells and Vδ1 γδ T cells. These atypical Vδ1 γδ T cells have activity against CMV infected fibroblasts, and sequencing of their TCRs demonstrated remarkable oligoclonality suggestive of antigen driven proliferation. In a second group of patients that underwent reduced intensity allogeneic stem cell transplant for myeloid malignancies, CMV seropositivity of patient or donor is associated with increased lymphocyte counts at 3 months post transpant, particularly of CD8 and Vδ1 γδ T cell subsets. Survival analysis of these patients revealed that CMV seropositivity is associated with improved overall survival, due to a decreased relapse risk.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RC0254 Neoplasms. Tumors. Oncology (including Cancer)