Tsang, Chi Wai (2008)
Ph.D. thesis, University of Birmingham.
The current treatment of nasopharyngeal carcinoma (NPC), a tumour common in southern Chinese people, is dependent on chemo/radiosensitivity. Patients with early stages of the disease are usually chemo and radiosensitive with 5 years survival rates of 90% whereas, patients with late-stages of the disease or relapse have between 20-70% survival rates. These statistics indicate a need for a treatment to improve the overall survival rates in NPC patients, especially for those with relapse. Immunotherapy is a prime candidate for such treatment due to its association with Epstein-Barr Virus (EBV) infection, expression of EBV antigens in NPC tumour cells and the presence of EBV-specific T cells at the tumour site. More importantly, studies in other EBV-associated diseases strongly indicated that CD8+ T cell based immunotherapy targeting EBV antigens could control EBV infection and also tumour regression in some patients, however, most patients show poor tumour response rate due to ineffective maintenance of EBV-specific CD8+ T cells. Studies have also shown that CD4+ T cells are important in the control of viral infection by maintaining an effective CD8+ T cell response and as effectors in its own right. CD4+ T cell responses to EBV antigens have only been studied in the Caucasian population and not in Chinese people where NPC incidence is high. This thesis work was prompted with these points in mind. In this thesis, the screening in 25 Caucasian donors (24 donors are EBV-seropositive and 1 donor was EBV-seronegative at the time of this study) for T cell responses (CD8+ and CD4+) against the predicted BART products and BARF1 protein. The BART and BARF1 transcripts are expressed in NPC tumour cells, but their expression as proteins have never been identified until Kienzle et al (1998) reported the finding of CD8+ T cell response to one of the products encoded by the BART transcript, BARF0. In this study, no CD8+ or CD4+ T cell responses were detected against the BART products or to BARF1 protein, and concluded that if responses do exist, they are probably rare responses and would have little or no immunotherapeutic value. The attention of this thesis work was then shifted to studying an EBV protein that is uniformly identified in NPC tumour cells, Epstein-Barr virus nuclear antigen (EBNA) 1. CD4+ T cell response against EBNA1 has been studied in the Caucasian population, however, little is known about CD4+ T cell epitopes presented by HLA alleles in Chinese people. In this study, CD4+ T cell responses in 78 healthy Chinese EBV carriers were analyzed and found marked focusing of epitopes in the EBNA1 C-terminal region, including a DP5-restricted epitope recognized by almost half of the donors tested. More importantly, EBNA1-specific CD4+ T cell clones to this DP5-restricted epitope could recognize EBNA1-expressing, DP5-positive target cells. However, further studies are required to determine the role of these EBNA1-specific CD4+ T cells in T cell based therapy.
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