Gricks, Clair; (2001) Lymphoma immunoglobulin idiotype derived peptides as targets for cytotoxic T cells. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Specific immune responses against human cancers require targeting of tumour specific or tumour associated antigens. In B cell lymphomas, surface immunoglobulin (sIg) provides a tumour specific target due to its unique method of synthesis, which involves gene rearrangement, addition of random nucleotides and somatic hypermutation. Immunotherapeutic strategies in B cell lymphoma have involved immunisation with the sIg variable region protein or DNA sequence leading to antibody production, rare cellular and infrequent clinical responses. This thesis analysed whether the sig variable region expressed by B cell lymphomas had the potential to generate a cytotoxic T cell response based on the rules governing MHC class I peptide presentation. The lymphoma derived sig variable regions from 40 patients were cloned and sequenced. Using bioinformatics databases and published literature, the variable regions were screened for the presence of peptides with the correct motifs to bind to the patients' autologous HLA class I molecules. To ensure tumour specificity, peptides that incorporated an amino acid change due to somatic hypermutation or covered a VD or DJ junction were chosen in preference to those coded by germline sequences. Peptides from 19 patients, restricted by 4 different HLA class I alleles, were analysed for their binding capability with in vitro binding assays. Selected peptides from the sIg variable region of 16 out of 19 patients showed binding to the patients' self HLA type. Peripheral blood mononuclear cells from 10 patients were stimulated with self and non-self lymphoma peptides to determine the presence of pre-existing immunity. Three out of ten patients showed a response to their lymphoma sig derived peptides. This thesis describes the discovery of unique HLA class I binding peptides present in the sig variable region derived from B cell lymphomas and may have important implications for vaccine design.

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