Engler Olivier B, Strasser Ingrid, Naisbitt Dean J, Cerny Andreas, Pichler Werner J
Division of Allergology, Clinic for Rheumatology and Clinical Immunology/Allergology, University of Bern, Inselspital, 3010 Bern, Switzerland.
Toxicology. 2004 Apr 1;197(1):47-56. doi: 10.1016/j.tox.2003.12.008.
Drugs can interact with T cell receptors (TCR) after binding to peptide-MHC structures. This binding may involve the formation of a stable, covalent bond between a chemically reactive drug and MHC or the peptide embedded within. Alternatively, if the drug is chemically inert, the binding may be non-covalent and readily reversible. Both types of drug presentation account for a substantial number of adverse side effects to drugs. Presently no tests are available to predict the ability of chemically inert drugs to stimulate an immune response. Here we present data on the successful induction of a primary T cell immune response in vitro against a chemically inert drug using blood from healthy individuals, previously not exposed to the drug. Blood lymphocytes were stimulated by the chemically inert drug sulfamethoxazole and the protein-reactive drug-metabolite sulfamethoxazole-nitroso in the presence of IL-2. 9/10 individuals reacted in response to sulfamethoxazole-nitroso, but only three reacted to the chemically inert compound sulfamethoxazole. Drug reactive T cells could be detected after 14-35 days of cell culture by drug-specific proliferation or cytotoxicity, which was MHC-restricted. These cells were CD4, CD8 positive or CD4/CD8 double positive and T cell clones generated secreted Th0 type cytokines. Drug interaction lead to down-regulation of specific TCR. These data confirm the ability of chemically inert drugs to stimulate certain T cells by their TCR and may provide the opportunity to screen new drugs for their ability to interact with TCRs.
药物与肽 - 主要组织相容性复合体（MHC）结构结合后可与T细胞受体（TCR）相互作用。这种结合可能涉及化学反应性药物与MHC或嵌入其中的肽之间形成稳定的共价键。或者，如果药物是化学惰性的，这种结合可能是非共价的且易于逆转。这两种药物呈现方式都导致了大量的药物不良反应。目前尚无测试可预测化学惰性药物刺激免疫反应的能力。在此，我们展示了使用健康个体（此前未接触过该药物）的血液在体外成功诱导针对化学惰性药物的原发性T细胞免疫反应的数据。在白细胞介素 - 2存在的情况下，化学惰性药物磺胺甲恶唑和蛋白质反应性药物代谢物磺胺甲恶唑 - 亚硝基刺激血液淋巴细胞。10名个体中有9名对磺胺甲恶唑 - 亚硝基有反应，但只有3名对化学惰性化合物磺胺甲恶唑有反应。通过药物特异性增殖或细胞毒性在细胞培养14 - 35天后可检测到药物反应性T细胞，这是MHC限制的。这些细胞为CD4、CD8阳性或CD4/CD8双阳性，并且产生的T细胞克隆分泌Th0型细胞因子。药物相互作用导致特定TCR的下调。这些数据证实了化学惰性药物通过其TCR刺激某些T细胞的能力，并可能为筛选新药与TCR相互作用的能力提供机会。
