Giest, S.; (2008) Detection, monitoring & clonal characterisation of human cytomegalovirus specific CD8+ T cells in hematopoietic stem cell transplant patients. Doctoral thesis , University of London.

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Abstract

The human cytomegalovirus (CMV) can cause significant morbidity and mortality in haematopoietic stem cell transplant (HSCT) patients. The immunosuppressed state of the hosts facilitates dissemination of the virus and disease. In contrast, CD8+ T cells in healthy individuals control viral dissemination and maintain a balance between antiviral host defence and replication of the virus that leads to viral latency with sporadic, harmless reactivations. Current pharmacological intervention in the HSCT setting is associated with significant toxicity and is counteracted by the occurrence of resistant viral strains. Alternative approaches, such as adoptive therapy of CMV specific CD8+ T cells are of great interest in the field. So far, levels of such cells correlating with protection against CMV disease in patients were only shown for cells targeting two different viral epitopes. The project described in this thesis investigates CD8+ T cell responses to several common CMV targets presented by different human leukocyte antigens in the HSCT setting. Results demonstrate significant differences between the numbers of different CMV specific CD8+ T cells that, in the presence of CD4+ T cell help, inversely correlate with the ability to detect CMV reactivation. Findings also demonstrate significant differences in the diversity of T cell receptors (TCRs) used by the different CMV specific CD8+ T cells isolated from HSCT patients. These findings are clinically relevant in that the quantity of cells shown to correlate with protection against CMV could be used as a marker for monitoring patients' immune status towards CMV. This may aid clinical decision making to limit pharmacological intervention to those patients at highest risk for the development of CMV disease. It may also aid the monitoring of the effectiveness of adoptive therapy trials. Therapeutic use of cells with high TCR diversity may be advantageous over other cells in that they may impede the development of CMV immune escape in patients.

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