T-cells, the drivers of adaptive immunity, have great therapeutic potential. However, there are still many unknowns about how they are activated. It is well understood that T-cells respond to antigens which have been processed and presented as antigenic peptides by molecules called “human leukocyte antigens” (HLA). However, chemical compounds such as drugs can interfere with this process, resulting in the formation of neo-antigens which have not been seen by the immune system before. For example, reactive drugs (metabolites) can covalently bind to proteins which can be processed and presented as haptenated-peptides by HLA proteins on the surface of antigen presenting cells. These haptenated-peptides, different from self-peptides have great potential to induce drug-specific immune reactions. This potentially harms self- tissues and is termed drug hypersensitivity. In this project, we aim to develop novel techniques to investigate binding of haptenated-peptides to class I HLA proteins and evaluate their immunogenicity. To achieve this, peptide libraries containing drug-modified peptides will be generated through protease digestion of model proteins treated with reactive drugs (metabolites). These peptide libraries will be subsequently characterised by mass spectrometry-based methods. Chemical compounds that have known genetic associations with specific HLA alleles will be used as model compounds to explore pathways of neo-antigen formation. Binding of drug-haptenated peptides to HLA molecules will be evaluated using protein arrays comprising immobilised HLA class I proteins. Lastly, the potential T-cell immunity of identified neo-antigens will be assessed using human T-cells from healthy volunteers and hypersensitivity patients.
Please apply via https://www.liverpool.ac.uk/study/postgraduate-research/how-to-apply/
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