Biological and clinical significance of chronic herpes virus infection in patients undergoing treatment for myeloid malignancies

Lewis, David John (2015). Biological and clinical significance of chronic herpes virus infection in patients undergoing treatment for myeloid malignancies. University of Birmingham. Ph.D.

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Abstract

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.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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