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

应用体外细胞系统研究药物特异性 T 细胞对靶组织的杀伤作用

• 批准号: 1961494
• 金额: --
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1961494
• 关键词: Application; vitro; cell; based; system

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.

由于药物过敏的性质，药物过敏通常在给大量人群使用药物之前不会被检测到。除了对人类安全的风险外，在这么晚的阶段停药对Pharma来说是巨大的成本，还会延长患者的时间，直到开发出更安全的药物。据估计，发现和开发一种药物的成本约为9亿美元，大约需要13年时间。因此，通过开发评估药物免疫原性的分析方法来减少后期药物的退出，将减少将更安全的药物推向市场的成本和时间，使制药业和患者受益。已从过敏患者的血液和组织中分离出药物特异性T细胞。药物与特定的人类白细胞抗原分子结合后激活这些细胞，导致细胞因子和细胞溶解分子的分泌。学术导师对药物过敏的化学和细胞基础有丰富的经验。为了在体外模拟这种反应，我们从1000名健康捐赠者身上建立了一个HLA型PBMC库，并设计了研究药物激活幼稚T细胞的方法。尽管如此，将抗原信号转化为组织损伤所需的免疫和患者因素的基本知识仍然缺乏。在博士生期间，候选人将探索支持药物过敏的基础科学，并定义与组织损伤发展相关的免疫学参数。该项目将设在药物安全科学研究中心(https://www.liverpool.ac.uk/drug-safety/).)我们是利物浦大学独一无二的研究中心，致力于了解临床上重要的药物不良反应的机制。我们将利用来自健康志愿者的药物诱导的T细胞表达相关的HLA风险等位基因，并诱导来自相同捐赠者的多能干细胞肝细胞/角质形成细胞系。我们将评估药物的免疫原性，还将整合组织和免疫细胞，以研究T细胞的激活和对靶组织的杀伤作用。以下问题将被解决：a.哪些药物以人类白细胞抗原等位基因受限的方式激活T细胞？被激活的T细胞的表型和功能是什么？C.药物是如何激活T细胞的？以及D.哪些信号通路参与T细胞介导的组织损伤？只有回答了这些问题，我们才有希望了解药物是如何导致这种医源性疾病的，并开发出预测免疫原性的测试方法。

项目成果

T cell mediated hypersensitivity to previously tolerated iodinated contrast media precipitated by introduction of atezolizumab.

• DOI: 10.1136/jitc-2021-002521
• 发表时间: 2021-05
• 期刊: Journal for immunotherapy of cancer
• 影响因子: 10.9
• 作者: Hammond S;Olsson-Brown A;Gardner J;Thomson P;Ali SE;Jolly C;Carr D;Ressel L;Pirmohamed M;Naisbitt D
• 通讯作者: Naisbitt D

Identification of flucloxacillin-modified hepatocellular proteins: implications in flucloxacillin-induced liver injury.

• DOI: 10.1093/toxsci/kfad015
• 发表时间: 2023-03-20
• 期刊: Toxicological sciences : an official journal of the Society of Toxicology

Prospective observational study of SARS-CoV-2 infection, transmission and immunity in a cohort of households in Liverpool City Region, UK (COVID-LIV): a study protocol.

• DOI: 10.1136/bmjopen-2020-048317
• 发表时间: 2021-03-17
• 期刊: BMJ open
• 影响因子: 2.9
• 作者: Setiabudi W;Hungerford D;Subramaniam K;Vaselli NM;Shaw VE;Wilton M;Vivancos R;Aston S;Platt G;Moitt T;Jones AP;Gabbay M;Buchan I;Carrol ED;Iturriza-Gomara M;Solomon T;Greenhalf W;Naisbitt DJ;Adams ER;Cunliffe NA;Turtle L;French N;COVID-LIV Study Group
• 通讯作者: COVID-LIV Study Group

Investigation of SARS-CoV-2 faecal shedding in the community: a prospective household cohort study (COVID-LIV) in the UK.

• DOI: 10.1186/s12879-021-06443-7
• 发表时间: 2021-08-09
• 期刊: BMC infectious diseases
• 影响因子: 3.7
• 作者: Vaselli NM;Setiabudi W;Subramaniam K;Adams ER;Turtle L;Iturriza-Gómara M;Solomon T;Cunliffe NA;French N;Hungerford D;COVID-LIV Study Group
• 通讯作者: COVID-LIV Study Group

T cell assays differentiate clinical and subclinical SARS-CoV-2 infections from cross-reactive antiviral responses.

• DOI: 10.1038/s41467-021-21856-3
• 发表时间: 2021-04-06
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Ogbe A;Kronsteiner B;Skelly DT;Pace M;Brown A;Adland E;Adair K;Akhter HD;Ali M;Ali SE;Angyal A;Ansari MA;Arancibia-Cárcamo CV;Brown H;Chinnakannan S;Conlon C;de Lara C;de Silva T;Dold C;Dong T;Donnison T;Eyre D;Flaxman A;Fletcher H;Gardner J;Grist JT;Hackstein CP;Jaruthamsophon K;Jeffery K;Lambe T;Lee L;Li W;Lim N;Matthews PC;Mentzer AJ;Moore SC;Naisbitt DJ;Ogese M;Ogg G;Openshaw P;Pirmohamed M;Pollard AJ;Ramamurthy N;Rongkard P;Rowland-Jones S;Sampson O;Screaton G;Sette A;Stafford L;Thompson C;Thomson PJ;Thwaites R;Vieira V;Weiskopf D;Zacharopoulou P;Oxford Immunology Network Covid-19 Response T Cell Consortium;Oxford Protective T Cell Immunology for COVID-19 (OPTIC) Clinical Team;Turtle L;Klenerman P;Goulder P;Frater J;Barnes E;Dunachie S
• 通讯作者: Dunachie S