Hausmann Oliver, Schnyder Benno, Pichler Werner J
Division of Allergology, Department of Rheumatology, Clinical Immunology and Allergology, Inselspital, CH-3010 Bern, Switzerland.
Handb Exp Pharmacol. 2010(196):29-55. doi: 10.1007/978-3-642-00663-0_2.
Immune reactions to drugs can cause a variety of diseases involving the skin, liver, kidney, lungs, and other organs. Beside immediate, IgE-mediated reactions of varying degrees (urticaria to anaphylactic shock), many drug hypersensitivity reactions appear delayed, namely hours to days after starting drug treatment, showing a variety of clinical manifestations from solely skin involvement to fulminant systemic diseases which may be fatal. Immunohistochemical and functional studies of drug-specific T cells in patients with delayed reactions confirmed a predominant role for T cells in the onset and maintenance of immune-mediated delayed drug hypersensitivity reactions (type IV reactions). In these reactions, drug-specific CD4+ and CD8+ T cells are stimulated by drugs through their T cell receptors (TCR). Drugs can stimulate T cells in two ways: they can act as haptens and bind covalently to larger protein structures (hapten-carrier model), inducing a specific immune response. In addition, they may accidentally bind in a labile, noncovalent way to a particular TCR of the whole TCR repertoire and possibly also major histocompatibility complex (MHC)-molecules - similar to their pharmacologic action. This seems to be sufficient to reactivate certain, probably in vivo preactivated T cells, if an additional interaction of the drug-stimulated TCR with MHC molecules occurs. The mechanism was named pharmacological interaction of a drug with (immune) receptor and thus termed the p-i concept. This new concept may explain the frequent skin symptoms in drug hypersensitivity to oral or parenteral drugs. Furthermore, the various clinical manifestations of T cell-mediated drug hypersensitivity may be explained by distinct T cell functions leading to different clinical phenotypes. These data allowed a subclassification of the delayed hypersensitivity reactions (type IV) into T cell reactions which, by releasing certain cytokines and chemokines, preferentially activate and recruit monocytes (type IVa), eosinophils (type IVb), or neutrophils (type IVd).
药物免疫反应可引发多种累及皮肤、肝脏、肾脏、肺及其他器官的疾病。除了即刻发生的不同程度的IgE介导反应（从荨麻疹到过敏性休克）外，许多药物超敏反应表现为延迟性，即在开始药物治疗数小时至数天后出现，临床表现多样，从仅累及皮肤到暴发性全身性疾病，后者可能致命。对延迟反应患者的药物特异性T细胞进行免疫组织化学和功能研究证实，T细胞在免疫介导的延迟性药物超敏反应（IV型反应）的发生和维持中起主要作用。在这些反应中，药物特异性CD4+和CD8+ T细胞通过其T细胞受体（TCR）被药物刺激。药物可通过两种方式刺激T细胞：它们可作为半抗原与较大的蛋白质结构共价结合（半抗原-载体模型），诱导特异性免疫反应。此外，它们可能以不稳定的非共价方式偶然结合到整个TCR库中的特定TCR上，也可能与主要组织相容性复合体（MHC）分子结合——类似于它们的药理作用。如果药物刺激的TCR与MHC分子发生额外相互作用，这似乎足以重新激活某些可能在体内已预激活的T细胞。该机制被命名为药物与（免疫）受体的药理相互作用，因此称为p-i概念。这一新概念可能解释口服或注射用药物超敏反应中常见的皮肤症状。此外，T细胞介导的药物超敏反应的各种临床表现可能由导致不同临床表型的不同T细胞功能来解释。这些数据允许将延迟性超敏反应（IV型）细分为T细胞反应，这些反应通过释放某些细胞因子和趋化因子，优先激活和募集单核细胞（IVa型）、嗜酸性粒细胞（IVb型）或中性粒细胞（IVd型）。
