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Title: Immunogenetic analysis of B-cell malignancies and the clinical application of DNA idiotypic vaccines
Author: McCarthy, Helen
ISNI:       0000 0001 3622 8929
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2004
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The first part of this thesis focuses on immunogenetic analysis of tumour idiotypes and their generation to gain further insight into the nature of the tumour antigen and the cell of origin. Follicular lymphoma (FL) and chronic lymphocytic leukaemia (CLL) were studied. Most patients with FL have somatically mutated V genes, consistent with location in the germinal centre site. Remarkably, this study showed 79% of these lymphomas had potential N-glycosylation sites introduced into their V genes as a result of somatic hypermutation. One possibility is that added carbohydrate in the variable region may interact with elements in the germinal centre environment and be critical for tumour behaviour. The maturation stage of CLL is more controversial. It consists of two prognostic subsets, distinguished by the incidence of somatic mutations in the Ig V-genes. Activation induced cytidine deaminase (AID), a protein essential for somatic hypermutation, is expressed by germinal centre B-cells in which this process occurs. Surprisingly, analysis of AID mRNA in CLL showed that cases with unmutated Ig V genes express high levels. In addition, transcripts of AID splice variants were detectable. This raises the possibility that the unmutated subset arises from antigen-experienced B-cells rather than naïve B-cells. The second part of this thesis focuses on the clinical application of DNA idiotypic vaccines in the treatment of B-cell malignancies. As with any vaccine, the clinical setting is critical and requires adequate immune capacity. The integrity of the immune system in patients with B-cell malignancies was therefore assessed by measuring their antibody response to vaccination with a conventional protein vaccine, tetanus toxoid. Response rates, as measured by a two fold increase in baseline values were 57% (8/14) in CLL stage A, 71% (11/14) in the diffuse large cell lymphoma and 72% (8/11) FL patients.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available