Understanding and preventing HLA-associated drug reactions

了解和预防 HLA 相关药物反应

基本信息

批准号：
9100798
负责人：
Elizabeth Phillips
金额：
$ 60.77万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9100798
关键词：
Accounting Address Alleles Antigens Asians Binding CD8B1 gene Carbamazepine Cell Separation Cells Chronic Clinical Research Cloning Cross Infection Cytomegalovirus DNA Development Disease Drug Design Drug Hypersensitivity Drug effect disorder Drug usage Eosinophilia Epitopes Genomics Glean Guidelines HIV HLA Antigens HLA-B Antigens Herpesviridae Human Human Herpesvirus 4 Hypersensitivity Immune Immunity In Vitro Life Mediating Modeling Molecular Morbidity - disease rate Open Reading Frames Organ Organ Specificity Organ Transplantation Organ failure Pathway interactions Patients Peptides Pharmaceutical Preparations Pharmacotherapy Phenotype Population Precision Phenomics Predictive Value Predisposition Prevention Reaction Sampling Sorting - Cell Movement Specificity Stevens-Johnson Syndrome Structure Symptoms Syndrome T cell response T memory cell T-Cell Antigen Receptor Specificity T-Cell Receptor T-Lymphocyte Testing Toxic Epidermal Necrolysis Translations Uncertainty Viral Work abacavir base case control clinical practice cost deep sequencing drug development improved in vivo insight mortality novel prevent repository research study risk variant screening skin disorder

项目摘要

Understanding and preventing HLA-associated drug reactions Immunologically-mediated adverse drug reactions (IM-ADRs) contribute disproportionately to drug- related morbidity and mortality and the cost and uncertainty of drug development. T-cell mediated drug hypersensitivity reactions are a subset of IM-ADEs that are severe and life-threatening, causing severe skin disease such as Stevens-Johnson Syndrome/toxic epidermal necrolysis (SJS/TEN), and organ failure. Severe T-cell mediated drug hypersensitivity syndromes have recently been associated with specific class I and/or II HLA alleles which has led to translational pathways for screening and prevention as well as great insight into their immunopathogenesis. The best example is the current widespread use of the HLA class I allele HLA- B*57:01 as a screening test prior to abacavir prescription in routine HIV clinical practice. We have made significant progress in defining the mechanistic basis of the predisposition of HLA-B*57:01 carriers to abacavir hypersensitivity which now has created a translational roadmap to define further the immunopathogenetic mechanisms of other severe HLA-associated T-cell mediated drug hypersensitivity syndromes. Notably, this recent work based on the abacavir model suggests that drugs rapidly and non-covalently bind to an HLA allele and alter the repertoire of self-peptides binding to the allele, creating a vigorous CD8+ T cell response. Abacavir specific CD8+ T-cell responses can be reproduced in-vitro in 100% of HLA-B*57:01 positive abacavir- naïve healthy donors. A key question central to the mechanism of HLA-associated IM-ADRs, and not explained by the altered peptide repertoire model, is why in vivo hypersensitivity generally occurs in only a small proportion of those carrying an HLA-risk allele and what determines the organ specificity of the hypersensitivity. This understanding is integral to the development of prediction and prevention models for severe T-cell mediated drug hypersensitivity. We will address this fundamental question through parallel studies of the T-cell receptor (TCR) usage and the T-cell antigen specificities of the relevant T cells. In Specific Aim 1 we will identify the primary TCR used by T cells in precisely phenotyped drug hypersensitive patients but not HLA-matched drug tolerant controls. We will then define in Specific Aim 2 anti-viral T cells directed against chronic prevalent human herpes viruses (HHV) present in these drug hypersensitive patients but not HLA-risk allele matched drug-tolerants and will focus on stored cell samples from HLA-B*57:01 positive abacavir hypersensitive and HLA-B*15:02 positive SJS/TEN patients. Finally in Specific Aim 3 to test the heterologous immune model, we will identify anti-viral T cells in drug hypersensitive patients that cross- recognize drug in the context of the defined HLA risk allele. The results of these studies will inform strategies for the prediction of severe HLA-associated IM-ADRs and guide drug development and design.

了解和预防 HLA 相关药物反应免疫介导的药物不良反应（IM-ADR）对药物不良反应的贡献不成比例。相关的发病率和死亡率以及 T 细胞介导的药物开发的成本和不确定性。超敏反应是 IM-ADE 的一个子集，严重且危及生命，会导致严重的皮肤病史蒂文斯-约翰逊综合征/中毒性表皮坏死松解症 (SJS/TEN) 等疾病和器官衰竭。 T 细胞介导的药物超敏综合征最近与特定的 I 类和/或 II 类药物过敏综合征相关 HLA 等位基因导致了筛查和预防的转化途径以及对最好的例子是目前广泛使用的 HLA I 类等位基因 HLA-。 B*57:01 作为常规 HIV 临床实践中阿巴卡韦处方前的筛查测试。在确定 HLA-B*57:01 携带者对阿巴卡韦易感性的机制基础方面取得重大进展超敏反应现在已经创建了一个转化路线图来进一步定义免疫病理学其他严重的 HLA 相关 T 细胞介导的药物过敏综合征的机制值得注意的是。最近基于阿巴卡韦模型的研究表明，药物可快速且非共价地与 HLA 等位基因结合并改变与等位基因结合的自肽库，产生强烈的 CD8+ T 细胞反应。阿巴卡韦特异性 CD8+ T 细胞反应可在 100% HLA-B*57:01 阳性阿巴卡韦体外重现幼稚的健康捐赠者是 HLA 相关 IM-ADR 机制的核心问题，而不是由改变的肽库模型解释，这就是为什么体内超敏反应通常只发生在携带 HLA 风险等位基因的人中的一小部分以及决定其器官特异性的因素这种理解对于开发超敏反应的预测和预防模型至关重要。严重的 T 细胞介导的药物超敏反应我们将通过平行解决这个基本问题。 T 细胞受体 (TCR) 使用和相关 T 细胞的 T 细胞抗原特异性的研究。具体目标 1 我们将鉴定 T 细胞在精确表型药物过敏中使用的主要 TCR 然后我们将在特定目标 2 中定义抗病毒 T 细胞。针对这些药物过敏患者中存在的慢性流行人类疱疹病毒 (HHV) 但不是 HLA 风险等位基因匹配的耐药性，并将重点关注来自 HLA-B*57:01 阳性的储存细胞样本最后在特定目标 3 中对阿巴卡韦过敏且 HLA-B*15:02 阳性的 SJS/TEN 患者进行测试。异源免疫模型，我们将鉴定药物过敏患者体内的抗病毒 T 细胞在定义的 HLA 风险等位基因的背景下识别药物这些研究的结果将为策略提供信息。用于预测严重的 HLA 相关 IM-ADR 并指导药物开发和设计。