Application of an in vitro cell-based system to investigate the killing of target tissue by drug-specific T-cells

Due to their nature, drug allergy is usually not detected until a drug is administered to a large population. As well as a risk to human safety, the withdrawal of drugs at such a late stage is of great cost to Pharma, and also prolongs the time for the patient until a safer drug is developed. The cost of discovering and developing a drug is estimated to be about $900 million, and takes approximately 13 years. Thus reducing late-stage drug withdrawals through the development of assays to assess immunogenicity of drugs would reduce the cost and time to bring safer drugs to the market, benefitting the pharmaceutical industry and patients. Drug-specific T-cells have been isolated from blood and tissue of allergic patients. Activation of these cells with the drug bound to specific HLA molecules results in the secretion of cytokines and cytolytic molecules. The academic supervisors have extensive experience characterizing the chemical and cellular basis of drug allergy. To model such reactions ex vivo we have generated an HLA-typed bank of PBMC from 1000 healthy donors and designed methods to study the activation naïve T-cells with drugs. Despite this, essential knowledge of the immune and patient factors required to convert the antigenic signal into tissue injury is missing. During this PhD studentship, the candidate will explore the fundamental science underpinning drug allergy and define the immunological parameters associated the development of tissue injury. The project will be based in the MRC Centre for Drug Safety Science (https://www.liverpool.ac.uk/drug-safety/). We are a unique research centre at The University of Liverpool dedicated to understanding the mechanisms of clinically-important adverse drug reactions. We will utilize drug-primed T-cells from healthy volunteers expressing relevant HLA risk alleles and induced pluripotent stem cell hepatocytes/keratinocytes-lines derived from the same donors. We will assess the immunogenicity of drugs, but also integrate the tissue and immune cells to investigate T-cell activation and the killing of target tissue. The following questions will be addressed: A. Which drugs activate T-cells in an HLA-allele-restricted manner? B. What is the phenotype and function of the activated T-cells? C. How do drugs activate T-cells? and D. Which signalling pathways are involved in T-cell-mediated tissue injury? Only by answering these questions can we hope to understand how drugs cause this form of iatrogenic disease and develop assays to predict immunogenicity.