Understanding and preventing HLA-associated drug reactions

认识和预防人类白细胞抗原相关药物反应 免疫介导的药物不良反应(IM-ADR)对药物的贡献不成比例。 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细胞介导的药物 过敏性反应是IM-ADE的一个子集，严重并危及生命，导致严重的皮肤 疾病，如史蒂文斯-约翰逊综合征/中毒性表皮坏死松解症(SJS/TEN)，以及器官衰竭。严重者 最近，T细胞介导的药物超敏综合征与特定的I类和/或II类相关 人类白细胞抗原(HL A)等位基因，为筛查和预防提供了翻译途径，并对 它们的免疫致病机制。最好的例子是目前广泛使用的人类白细胞抗原I类等位基因-- B*57：01作为常规HIV临床实践中开出阿巴卡韦处方前的筛查试验。我们已经做出了 确定人类白细胞抗原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翻译路线图，以进一步定义免疫病理 其他严重的人类白细胞抗原相关T细胞介导的药物超敏反应综合征的机制。值得注意的是，这 基于abacavir模型的最新研究表明，药物可以快速和非共价结合到一个人类白细胞抗原等位基因。 并改变与等位基因结合的自体多肽的谱系，产生强有力的CD8+T细胞反应。 在人类白细胞抗原B*57：01阳性患者中，阿巴卡韦特异性CD8+T细胞反应可在体外100%复制。 天真健康的捐赠者。人类白细胞抗原相关IM-ADRs机制的核心问题，而不是 由改变后的多肽谱系模型解释，为什么体内的超敏反应通常只发生在 携带人类白细胞抗原风险等位基因的一小部分人，以及是什么决定了 过敏症。这一理解对于发展预测和预防模型是不可或缺的。 重度T细胞介导的药物超敏反应。我们将通过并行的方式解决这一根本问题 研究T细胞受体(TCR)的用途和相关T细胞的T细胞抗原特异性。在……里面 具体目标1我们将确定T细胞在精确表型药物超敏反应中使用的主要TCR 患者，但不是人类白细胞抗原匹配的耐药对照组。然后我们将在特定的目标中定义2个抗病毒T细胞 针对这些药物过敏患者中存在的慢性流行的人类疱疹病毒(HHV) 但不匹配耐药患者的人类白细胞抗原风险等位基因，并将重点放在保存的来自人类白细胞抗原B*57：01阳性的细胞样本上 阿巴卡韦过敏和人类白细胞抗原B*15：02阳性SJS/10例。最后在具体目标3中测试 异源免疫模型，我们将在药物过敏患者中识别抗病毒T细胞，这些T细胞是交叉的。 根据已定义的人类白细胞抗原风险等位基因识别药物。这些研究的结果将为战略提供参考 用于预测严重的人类白细胞抗原相关的IM-ADRs，并指导药物的开发和设计。

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.