Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32611, USA.
Proc Natl Acad Sci U S A. 2012 Jun 19;109(25):9959-64. doi: 10.1073/pnas.1207934109. Epub 2012 May 29.
Idiosyncratic adverse drug reactions are unpredictable, dose-independent and potentially life threatening; this makes them a major factor contributing to the cost and uncertainty of drug development. Clinical data suggest that many such reactions involve immune mechanisms, and genetic association studies have identified strong linkages between drug hypersensitivity reactions to several drugs and specific HLA alleles. One of the strongest such genetic associations found has been for the antiviral drug abacavir, which causes severe adverse reactions exclusively in patients expressing the HLA molecular variant B57:01. Abacavir adverse reactions were recently shown to be driven by drug-specific activation of cytokine-producing, cytotoxic CD8(+) T cells that required HLA-B57:01 molecules for their function; however, the mechanism by which abacavir induces this pathologic T-cell response remains unclear. Here we show that abacavir can bind within the F pocket of the peptide-binding groove of HLA-B*57:01, thereby altering its specificity. This provides an explanation for HLA-linked idiosyncratic adverse drug reactions, namely that drugs can alter the repertoire of self-peptides presented to T cells, thus causing the equivalent of an alloreactive T-cell response. Indeed, we identified specific self-peptides that are presented only in the presence of abacavir and that were recognized by T cells of hypersensitive patients. The assays that we have established can be applied to test additional compounds with suspected HLA-linked hypersensitivities in vitro. Where successful, these assays could speed up the discovery and mechanistic understanding of HLA-linked hypersensitivities, and guide the development of safer drugs.
个体药物不良反应不可预测、与剂量无关且可能危及生命；这使其成为导致药物开发成本和不确定性的主要因素。临床数据表明，许多此类反应涉及免疫机制，遗传关联研究已经确定了几种药物过敏反应与特定 HLA 等位基因之间的紧密联系。发现的最强遗传关联之一是抗病毒药物阿巴卡韦，它仅在表达 HLA 分子变体 B57:01 的患者中引起严重不良反应。最近表明，阿巴卡韦不良反应是由药物特异性激活细胞因子产生的细胞毒性 CD8(+)T 细胞驱动的，这些细胞需要 HLA-B57:01 分子才能发挥功能；然而，阿巴卡韦诱导这种病理性 T 细胞反应的机制尚不清楚。在这里，我们表明阿巴卡韦可以结合 HLA-B*57:01 肽结合槽的 F 口袋内，从而改变其特异性。这解释了 HLA 相关的个体药物不良反应，即药物可以改变呈递给 T 细胞的自身肽谱，从而引起等效的同种反应性 T 细胞反应。事实上，我们鉴定了仅在存在阿巴卡韦的情况下呈递且被过敏患者的 T 细胞识别的特定自身肽。我们建立的检测方法可用于在体外测试具有疑似 HLA 相关过敏的其他化合物。如果成功，这些检测方法可以加快发现和阐明 HLA 相关过敏的机制，并指导更安全药物的开发。
