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T-cell responses to human cytomegalovirus in immune-impaired individuals.

Kopycinski, J.T.; (2006) T-cell responses to human cytomegalovirus in immune-impaired individuals. Doctoral thesis , University of London. Green open access

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Abstract

HCMV is a near-ubiquitous p-herpesvirus that asymptomatically infects the majority of immunocompetent adults. However, in the immunodeficient or the immunosuppressed, HCMV becomes a major cause of morbidity. Solid organ transplant recipients require immunosuppressive regimens prior to organ transplantation the resultant reduction in their T-cell responses leads to an increased risk of uncontrolled HCMV replication, which left unchecked is associated with HCMV disease. In this thesis we observed fluctuations of HCMV-specific CD4 and CD8 T-cell populations in 20 renal transplant patients during the six months following transplant using flow cytometry. The frequencies of these populations were related to incidences of viraemia. Patients suffering viraemic episodes post-transplant had significantly decreased HCMV-specific CD8+ cell responses when compared to individuals who remained HCMV PCR negative and a link was established between the absolute numbers of HCMV-specific CD4 cells and the size of the HCMV-specific CD8 response. Temporal increases in virus-specific CD8 responses were also observed, which corresponded with decreases in the incidences of HCMV viraemia after immunosuppressive regimens were reduced. Further work focused on the emergence of CTL-escape mutants in individuals who, despite having detectable HCMV epitope-specific CD8 responses failed to prevent viraemic episodes. Although no mutations were detected in the patients analysed, a substitution analysis was performed on a defined epitope to determine the possible effects of any substitutions on MHC I molecules binding and recognition by CTLs. Results showed a variety of substitutions could abrogate IFNy production by CTLs whilst binding and stabilising MHC I complexes. I also demonstrated for the first time that individuals suffering from common variable immunodeficiency (CVID) - who lack the capacity to mount their own B-cell responses, had detectable HCMV-specific T-cell responses and did not suffer symptomatic HCMV infection, indicating that control of HCMV replication could be mediated by the T-cell arm of the adaptive immune response.

Type: Thesis (Doctoral)
Title: T-cell responses to human cytomegalovirus in immune-impaired individuals.
Identifier: PQ ETD:592213
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: https://discovery.ucl.ac.uk/id/eprint/1444903
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