FREE PhD study and funding virtual fair REGISTER NOW FREE PhD study and funding virtual fair REGISTER NOW

Developing novel MHC protein array-based methods for non-clinical assessment of small-molecule immunogenicity


   Department of Pharmacology and Therapeutics

This project is no longer listed on FindAPhD.com and may not be available.

Click here to search FindAPhD.com for PhD studentship opportunities
  Dr Xiaoli Meng, Prof D Naisbitt, Mr Geoff Williams  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

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/


Funding Notes

The studentship is funded by the Faculty of Health and Life Sciences, University of Liverpool and GlaxoSmithKline (GSK, Hertfordshire, UK).

References

1. HLA Class-II. Restricted CD8(+) T Cells Contribute to the Promiscuous Immune Response in Dapsone-Hypersensitive Patients (2021), J invest Dermatol 141: 2412
2. Characterisation of naturally processed and presented drug-modified peptides that act as T cell antigens. (2020), Toxicol Sci 177: 454-456
3. HLA DRB1*15:01-DQB1*06:02-restricted human CD4+ T-cells are selectively activated with amoxicillin-peptide adducts. (2020), Toxicol Sci 178:115-126
4. Dapsone‐ and nitroso dapsone‐specific activation of T cells from hypersensitive patients expressing the risk allele HLA‐B*13:01. (2019), Allergy 74: 1533-1548
5. Exosomal transport of hepatocyte-derived drug-modified proteins to the immune system. (2019), Hepatology 70: 1732-1749
PhD saved successfully
View saved PhDs