Role of the AHR in cutaneous adverse drug reactions

药物不良反应（ADR）是常见的，通常对患者的健康构成严重威胁，并可能影响他们的治疗持续性。ADR主要分为靶向反应和脱靶反应。靶向反应非常常见，由药物的已知治疗和药理作用增强引起。相反，脱靶反应包括不可预测的免疫反应和非免疫反应。脱靶非免疫性ADR可能涉及先天免疫应答，但并非基于免疫记忆引起的特异性超敏反应。最近，申请人及其合作者证明，维罗非尼拮抗典型的芳烃受体（AHR）信号传导途径，导致出现呈现为炎性皮疹或光毒性反应的脱靶非免疫反应。AHR是一种转录因子，其在被多种配体激活后协调多种功能，所述配体包括外源性物质、天然产物、微生物组代谢物和（假）内源性分子。除了皮肤稳态，AHR途径控制免疫介导的皮肤反应，也参与皮肤病理过程，如特应性皮炎和斑块状银屑病。此外，AHR途径调节常见药物的代谢。AHR的激活刺激经典和非经典途径。典型和非典型AHR信号传导途径在健康皮肤中紧密平衡，从而有助于皮肤稳态。初步未发表的数据表明，不仅vemurafenib，而且还有几种其他药物作为AHR配体存在，并在体外显示出对AHR的拮抗活性。在拟定项目中，申请人旨在表征AHR在ADR中的作用，并提出调节AHR活性作为脱靶非免疫ADR的新机制的概念。为此，申请人将首先使用经验数据以及计算机预测模型来鉴定干扰AHR信号传导的药物（目的#1），其次确认AHR拮抗药物的生物学作用（目的#2），第三验证ADR患者生物材料中的AHR拮抗特征（目的#3），第四，建立基于细胞的诊断工具，以在体外鉴定AHR介导的药疹（目标4）。实验方法在申请人的实验室，他的合作者或杜塞尔多夫大学的核心设施中建立。项目意义：拟开展的项目将确定干扰AHR信号传导的临床相关药物。本项目的发现将增加我们对基于脱靶非免疫ADR的ADR诱导的分子和细胞途径的理解。本研究结果将提供新的翻译概念，以改善ADR的临床管理。

Adverse drug reactions (ADR) are common and often represent a serious threat to patients’ health and that may compromise their treatment continuation. ADR are mostly classified in on-target and off-target reactions. On-target reactions are very common and are caused by an augmentation of the known therapeutic and pharmacological action of a medication. In contrast, off-target reactions consist of unpredictable immune and non-immune reactions. Off-target non-immune ADR may involve innate immune responses but are not based on a specific hypersensitivity due to an immunological memory. Recently, the applicant and his collaborators demonstrated that vemurafenib antagonizes the canonical aryl hydrocarbon receptor (AHR) signaling pathway resulting in the development of an off-target non-immune reaction presenting as inflammatory skin rashes or phototoxic reactions. The AHR is a transcriptional factor that orchestrates multiple functions following its activation by a variety of ligands including xenobiotics, natural products, microbiome metabolites, and (pseudo-) endogenous molecules. Apart from skin homeostasis, the AHR pathway controls immune-mediated skin responses and is also involved in cutaneous pathological processes such as atopic dermatitis and plaque psoriasis. Moreover, the AHR pathway regulates the metabolism of common drugs. Activation of AHR stimulates canonical and non-canonical pathways. The canonical and the non-canonical AHR signaling pathways are tightly balanced in healthy skin thereby contributing to skin homeostasis. Preliminary unpublished data demonstrate that not only vemurafenib but also several other drugs present as AHR ligands and display antagonistic activity against the AHR in vitro. In the proposed project the applicant aims to characterize the role of the AHR in ADR and put forward the concept of modulating of AHR activity as a new mechanism of an off-target non-immune ADR. For this purpose, the applicant will first use empirical data as well as in silico-prediction models to identify drugs interfering with AHR-signaling (aim #1), second confirm the biologic effects of AHR-antagonistic drugs (aim #2), third validate AHR antagonism signatures in biomaterial of ADR patients ex vivo (aim #3), and fourth establish a diagnostic cell-based tool to identify AHR-mediated drug eruptions in vitro (aim #4). The experimental methods are established in the laboratories of the applicant, his collaborators or at the core facilities of the University of Düsseldorf. Significance of the project: The proposed project will identify clinically relevant drugs that interfere with AHR signaling. Findings of this project will increase our understanding of molecular and cellular pathways inducing ADR based on an off-target non-immune ADR. The results will provide new translational concepts to improve the clinical management of ADR.