Indirect effects of cytomegalovirus in kidney transplantation

Shabir, Shazia (2017). Indirect effects of cytomegalovirus in kidney transplantation. University of Birmingham. Ph.D.

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Abstract

Cytomegalovirus (CMV) infection is the most frequent and significant opportunistic infection in kidney transplant recipients. It is associated with direct (CMV disease) and indirect (rejection, poor graft survival) effects with resultant increases in morbidity and mortality. The mechanisms responsible for the indirect effects of CMV infection remain unclear.

In this thesis, the indirect effects of cytomegalovirus infection in kidney transplantation are studied. Firstly, the mechanism of CMV infection is investigated. Secondly, the mechanism of CMV associated kidney transplant damage is explored. Thirdly, an assessment for the role of CMV in causing immunosenescence within the kidney transplantation cohort is undertaken.

This thesis provides previously undescribed and direct evidence of immune hypo- responsiveness to latent CMV. I have shown CD4\(^+\)CD27\(^-\)CD28\(^{null}\) cells are pathognomonic of prior CMV exposure and have a role in glomerular endothelial cell damage, an effect which may be mediated by NKG2D. Higher CD4\(^+\)CD27\(^-\)CD28\(^{null}\) cell counts at 12 months post-transplantation predict a steeper decline in kidney allograft function thereafter. I provide novel insight into the ‘indirect’ effect of CMV in the pathogenesis of CD8\(^+\)CD28\(^{null}\) cells. My study is the first to demonstrate a temporal association between elevated CD8\(^+\)CD28\(^{null}\) cell frequencies and subsequent development of clinically relevant episodes of infection.

The findings from this thesis set the scene for future interventional research and therapeutic strategies.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):