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Title: Antibody-based strategies for identifying novel apoptotic-cell surface-associated molecules
Author: Tennant, Ian
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2005
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Defective clearance of apoptotic cells (ACs) is linked to autoimmune and inflammatory disease states such as systemic lupus erythematosus and cystic fibrosis. Relatively few markers exist for the ‘eat me’ signals displayed on the AC surface despite the great potential for such molecules as diagnostic or therapeutic reagents. In this work various antibody-based strategies were employed in an attempt to identify novel AC-specific epitopes. An initial strategy utilised a phage displayed antibody library containing a repertoire of ~108 antibody fragments encoded by human germline genes as an unbiased source of binding specificity. An alternative approach was based on the knowledge that receptors used by macrophages to recognise ACs also recognise pathogen-associated molecules. By looking for the ability of antibodies raised against pathogens to cross-react with ACs the hypothesis that cells undergoing apoptosis reveal molecular patterns that resemble those on pathogen related structures was tested. Screening of antibodies raised in vivo, that have previously been characterised as having specificity for pathogen-associated molecular patterns (PAMPs) revealed that some cross-react with cells undergoing apoptosis. One of these antibodies was found to bind an epitope found on the ubiquitously expressed ~40KDa precursor to Laminin-Binding-Protein (LBP/p40). These findings suggest that epitopes resembling PAMPs appear on the surface of mammalian cells as a result of apoptosis and that these epitopes can be found on endogenously expressed molecules which are normally excluded from the surface of viable cells. The ability of host receptors to cross-react with host and pathogen-associated epitopes in this way may lead to a greater understanding of the mechanisms of autoimmune reactions and allow design of approaches to stimulate the immune system for the treatment of cancer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available