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Title: Generation and testing of an anti-idiotype that acts as a surrogate antigen for oxidized LDL (OxLDL) in serological studies measuring anti-OxLDL antibodies
Author: Chang, Shang-Hung
ISNI:       0000 0004 2743 5792
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2010
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Atherosclerosis is thought to be mediated by immune response in which oxidized low density lipoprotein (OxLDL) is one of the major antigens. The exact linkage between anti-OxLDL antibodies and atherosclerosis, however, is controversial. One of the sources of this controversy is the inherently heterogeneous and complex nature of OxLDL as an antigen. This study aims to identify and characterise a new type of structurally definable surrogate antigen for OxLDL for use in serologic assays. The study applied two techniques for cloning antibodies. The first step was the generation of a monoclonal anti-OxLDL antibody, designated LO-1, by fusing mouse B cells and myeloma cells. The mouse used in this fusion was not immunized but fed with high fat diet to reflect the physiologic but hyperlipidemic immune environment. The second step was to use a phage display system (Tomlinson library of single chain variable antibody fragments) to screen anti-idiotypic antibodies (anti-id) against an anti-OxLDL monoclonal antibody generated from that mouse. The anti-id selected for further characterisation, was designated H3. This anti-id, which probably mimics both peptide and lipid components of OxLDL, was used as an antigen in a serologic assay (both in mice and humans) and compared with ordinary OxLDL antigens conventionally used by earlier researchers. Titres of antibodies against H3 correlated well with antibodies against malondialdehyde-conjugated LDL. Although the overall performance of anti-H3 antibodies was no better than conventional anti-OxLDL assays in predicting atherosclerosis, they showed an inverse relationship with the extent of left anterior descending coronary artery stenosis in patients with established coronary artery disease. This project has developed a novel approach to measuring OxLDL antibodies. The proposed unique mimicry of both the lipoprotein and the phospholipid components of OxLDL may reveal a functionally significant epitope of OxLDL that has not been successfully mapped by previously reported methodologies. The novel anti-id H3 and the corresponding mimetic region of OxLDL therefore provide new insight and new tools for future research on the humoral response related to atherosclerosis.
Supervisor: Haskard, Dorian Sponsor: Changgeng ji nian yi yuan
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral