Understanding and preventing HLA-associated drug reactions

了解和预防HLA相关的药物反应 免疫介导的药物不良反应（IM-ADR）对药物- 相关的发病率和死亡率以及药物开发的成本和不确定性。T细胞介导药物 超敏反应是IM-ADE的一个子集，严重且危及生命，可导致严重的皮肤 疾病如Stevens-Johnson综合征/中毒性表皮坏死松解症（SJS/TEN）和器官衰竭。严重 T细胞介导的药物超敏反应综合征最近与特定的I类和/或II类 HLA等位基因，这导致了翻译途径的筛选和预防，以及伟大的洞察， 它们的免疫发病机制。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试验。我们取得了 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了重大进展 超敏反应，现在已经创建了一个翻译路线图，以进一步定义免疫病理 其他严重HLA相关T细胞介导的药物超敏反应综合征的机制。值得注意的是， 基于阿巴卡韦模型的最新研究表明，药物可以快速地与HLA等位基因非共价结合 并改变与等位基因结合的自身肽库，产生强烈的CD 8 + T细胞反应。 阿巴卡韦特异性CD 8 + T细胞应答可以在100%的HLA-B*57：01阳性阿巴卡韦中体外重现。 天真健康的捐赠者HLA相关IM-ADR机制的一个关键问题， 由改变的肽库模型解释，是为什么体内超敏反应通常只发生在 一小部分携带HLA风险等位基因的人，以及决定器官特异性的因素， 超敏反应。这一认识是发展预测和预防模式不可或缺的， 严重的T细胞介导的药物超敏反应。我们将通过平行的方式解决这一基本问题， 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。在 具体目标1我们将鉴定T细胞在精确表型的药物过敏中使用的主要TCR。 患者，而不是HLA匹配的药物耐受对照。然后，我们将在特异性目标2中定义抗病毒T细胞 针对存在于这些药物过敏患者中的慢性流行性人类疱疹病毒（HHV） 但不包括HLA风险等位基因匹配的药物耐受者，并将重点关注来自HLA-B*57：01阳性的储存细胞样本 阿巴卡韦过敏和HLA-B*15：02阳性SJS/TEN患者。最后，在具体目标3中， 异源免疫模型，我们将确定抗病毒T细胞在药物过敏的患者， 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战略提供信息， 用于预测严重的HLA相关IM-ADR并指导药物开发和设计。

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.