Delayed drug hypersensitivity: models of T-cell stimulation
Delayed drug hypersensitivity: models of T-cell stimulation
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DOI：
10.1111/j.1365-2125.2010.03764.x
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发表时间：
2011-05-01
影响因子：
3.4
通讯作者：
Yerly, Daniel
中科院分区：
文献类型：
--
作者：
Adam, Jacqueline;Pichler, Werner J.;Yerly, Daniel
药物诱导的超敏反应可通过涉及药物特异性T细胞而引起多种严重疾病。这些反应中的许多已经被半抗原概念所解释，该概念假设小的化学化合物需要与蛋白质共价结合才能被免疫系统识别。由于其化学反应性，半抗原通过共价结合内源性蛋白质并形成所谓的半抗原-载体复合物来刺激先天免疫，所述半抗原-载体复合物是抗原性的并诱导T细胞应答。近年来，一个新的概念已经发展，因为药物诱导的超敏反应也被观察到与化学无反应的药物。这一概念意味着药物在T细胞受体（TCR）和主要组织相容性复合体（MHC）分子之间的直接和可逆的相互作用。因此，它被称为与免疫受体的药理学相互作用（p-i概念）。对药物反应性T细胞克隆（TCC）的早期观察让人相信药物首先结合T细胞受体，因为HLA分子可以交换而不影响药物反应性。然而，MHC分子总是需要TCC的完全激活。根据其强烈的HLA-B*5701关联，阿巴卡韦的最新数据表明，药物可以首先与MHC分子的肽结合沟结合。由此修饰的HLA分子然后可以被特异性T细胞识别。因此，可能发生基于p-i机制的两种类型的反应：一方面，药物可能优先直接结合TCR，而在具有强HLA缔合的确定病例中，药物可能直接结合MHC分子。
Drug-induced hypersensitivity reactions can cause a variety of serious diseases by involving drug-specific T-cells. Many of these reactions have been explained by the hapten concept, which postulates that small chemical compounds need to bind covalently to proteins to be recognized by the immune system. Due to their chemical reactivity, haptens stimulate the innate immunity by binding covalently to endogenous proteins and form so called hapten-carrier complexes, which are antigenic and induce T-cell responses. In recent years, a new concept has been developed since drug-induced hypersensitivity reactions were also observed with chemically unreactive drugs. This concept implies direct and reversible interactions of the drug between T-cell receptors (TCR) and major histocompatability complex (MHC) molecules. Therefore it was termed pharmacological interactions with immune receptors (p-i concept). Early observations on drug reacting T-cell clones (TCC) let believe that drugs bind first to the T-cell receptor since HLA molecules could be exchanged without affecting the drug reactivity. However, MHC molecules were always required for full activation of TCC. According to its strong HLA-B*5701 association, recent data on abacavir suggest that a drug could first bind to the peptide binding groove of the MHC molecule. The thereby modified HLA molecule can then be recognized by specific T-cells. Consequently, two types of reactions based on the p-i mechanism may occur: on the one hand, drugs might preferentially bind directly to the TCR, whereas in defined cases with strong HLA association, drugs might bind directly to the MHC molecule.