Aubert, G.; (2004) Molecular detection, monitoring and modulation of antigen specific immune responses. Doctoral thesis , University of London.

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Abstract

Stem cell transplantati.on (SCT) represents the only curative treatment option for leukaemia. The bone marrow or peripheral blood stem cells transferred in the transplant procedure restore immune functions, allowing the targeting of infected cells or cells expressing tumour antigens. Cytotoxic T lymphocytes (CTL), key mediators of antigen specific killing, were investigated in the context of cytomegalovirus (CMV) infection or chronic myeloid leukaemia (CML). CMV infection after SCT in the absence of effective immunological control or antiviral therapy is a significant cause of morbidity and mortality. HLA-A*0201 tetramer reagents were prepared with three candidate peptides and used to test healthy donor and SCT patient samples. Only T cells binding to the tetramer made with the predominant pp65 epitope (AE42: 495-503) were found for HLA-A*0201 healthy individuals and patients after SCT and correlated with the estimation of the responding T cell population to this peptide as measured by interferon-Tproduction. Parallel tetramer and viral load monitoring of patients at risk of CMV infection after SCT highlighted an inverse correlation between the state of replication of the virus and the number of CMV specific CTL. Presentation of a CML tumour specific peptide epitope in the context of HLA- A*0301 was demonstrated both at the surface of tumour positive cells lines and patient cells. HLA/peptide tetramer reagents were prepared with this peptide and used to screen CML patient samples. Low frequencies of peptide specific CTL were detected in some patients and could be stimulated in vitro. While donor lymphocytes infusions would improve CTL responses after SCT, they also carry the risk of graft versus host disease and may not comprise an effective CTL population targeted to the antigen of interest. A better outcome may be obtained by infusion of enriched and or expanded specific T cell populations. The enrichment, stimulation and expansion of CTL with HLA/peptide tetramer or modified tetramer complexes was examined, using the HLA-A*0201/CMV CTL response as a model. The use of HLA/peptide tetramers to monitor recipients of SCT has implications for the improvement of the treatment of CMV after SCT and the definition of targets and criteria for effective adoptive transfer. Furthermore, the use of HLA/peptide tetramers could be investigated in the assessment of anti-tumour CTL responses, in enhancing existing responses and possibly in inducing primary immune responses to viral pathogens and to tumours.

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