Understanding shared mechanisms of response to targeted therapies for eczema

特应性湿疹是一种常见的炎症性皮肤病，影响20%的儿童和10%的成人1,2。其特征是表皮屏障功能障碍和Th2炎症介质（IL-4/IL-13）的过量产生。最近的研究已经提供了针对这些免疫分子的治疗方法，dupilumab（一种单克隆抗体生物阻断IL-4和IL-13）和Janus激酶（JAK）抑制剂（下调多种细胞因子，包括IL-4和IL-13）显示出主要益处3。然而，这些高成本药物（每位患者每年约10,000英镑）增加了本已沉重的疾病经济负担。最近的一项网络荟萃分析进一步强调了药物反应和耐受性的个体异质性。患者经常循环使用多种药物来实现疾病控制，经历发作，感染，不良反应。超过60%的患者在使用dupilumab和JAK抑制剂后不能达到皮肤清洁或接近清洁的效果7-10。dupilumab的眼部副作用发生率超过50%，带状疱疹是JAK抑制剂最常见的感染并发症。这些问题反映了人们对这些药物如何起作用的了解有限。先前使用有限分辨率的微阵列和大量RNA-seq的研究表明，在治疗12-16周后，不同疗法的作用最终集中在对中心致病性Th2轴的共同抑制7,8。然而，缺乏头对头比较数据，缺乏早期治疗效果的机制研究。这导致对主要药物后果的理解不足，而不是抑制炎症级联反应的继发性/下游效应。美国国家卫生研究院资助的BEACON多臂试验是解决这一重要研究缺口的全球独特机会。从2023年第二季度开始（Smith联合领导），它将提供主要类别湿疹治疗的比较临床有效性、耐受性和成本效益的首个正面证据。在这种情况下，单细胞（包括单核）方法有可能为治疗行动9-11提供高分辨率的机制见解。这项技术的力量在癌症研究中得到了体现，它阐明了免疫治疗过程中肿瘤免疫浸润的演变。相反，在湿疹中，缺乏治疗效果的单细胞数据，也没有新的靶向治疗的比较分析13。问题：在湿疹中，介导对靶向治疗的共同反应的关键早期事件是什么？假设：不同的靶向治疗具有共同的早期作用机制，这些机制对湿疹中Th2抑制的最终效果至关重要。目的：交叉交叉靶向治疗dupilumab（生物）和JAK抑制剂在对这些药物表现出临床反应的beacon参与者中的早期作用。这将揭示早期共同的变化，推动湿疹的解决。目的1：利用单核RNA-seq （snRNA-seq）鉴定皮肤细胞亚群、细胞间相互作用和基因调控网络的早期变化，这些变化支持治疗作用，并集中于Th2轴抑制。目标2：定义支持皮肤治疗作用的细胞亚群和细胞-细胞相互作用的空间背景（如目标1所述）。目的3：通过来自BEACON队列的匹配血液样本的免疫谱分析来表征与血液中药物作用和反应相关的细胞亚群。

Atopic eczema is a common inflammatory skin disease, affecting 20% of children and 10% of adults1,2. It is characterised by epidermal barrier dysfunction and excessive production of Th2 inflammatory mediators (IL-4/IL-13).Recent research has delivered therapies targeting these immune molecules, with dupilumab (a monoclonal antibody biologic blocking IL-4 and IL-13) and Janus kinase (JAK) inhibitors (downregulating multiple cytokines, including IL-4 and IL-13) showing major benefit3. However, these high-cost drugs (~£10,000 per patient per year) add to the already substantial economic burden of disease. A recent network meta-analysis further highlighted inter-individual heterogeneity in drug response and tolerability4. Patients often cycle through multiple drugs to achieve disease control, experiencing flares, infection, adverse effects. More than 60% fail to achieve clear/nearly clear skin on dupilumab and JAK inhibitors7-10. Eye side-effects impact more than 50% of those on dupilumab and herpes zoster is the commonest infectious complication of JAK inhibitors11-13.These problems reflect the limited understanding of how these drugs work5,6. Prior studies using the limited resolution of microarray and bulk RNA-seq suggest the action of different therapies ultimately converge on shared suppression of the central pathogenic Th2 axis by 12-16 weeks of treatment7,8. There is, however, a lack of head-to head comparator data and a paucity of mechanistic research into early treatment effects. This has led to a poor understanding of primary drug consequences as opposed to secondary/downstream effects of inhibiting inflammatory cascades. The NIHR-funded BEACON multi-arm trial is a globally unique opportunity to address this important research gap.Commencing Q2 2023 (co-lead Smith), it will provide the first head-to-head evidence on comparative clinical effectiveness, tolerability and cost effectiveness of the major classes of eczema therapies. In this context, single cell (including single nuclear) methods have the potential to provide high resolution mechanistic insights into treatmentactions 9-11. The power of this technology is exemplified in cancer research, where it has illuminated the evolution of tumour immune infiltrates during immunotherapy9,12. Conversely, in eczema there is a paucity of single cell data on treatment effects and no comparative analyses of novel targeted therapies13. Question: What are the critical early events that mediate shared response to targeted therapies in eczema?Hypothesis: Different targeted therapies share early mechanisms of action that are critical to their ultimate effects on Th2 suppression in eczema.Objective: To intersect the early actions of the targeted therapies dupilumab (biologic) and JAK inhibitors in BEACONparticipants who show a clinical response to these drugs. This will uncover early shared changes that drive eczema resolution.Aim 1: Identify early changes in skin cell subpopulations, cell-cell interactions and gene regulatory networks that underpin treatment actions and converge upon Th2 axis suppression using single nuclear RNA-seq (snRNA-seq).Aim 2: Define the spatial context of the cell subpopulations and cell-cell interactions underpinning treatment actionsin skin (as identified in Aim 1). Aim 3: Characterise the cell subpopulations implicated in drug action and response in blood by immune profiling matched blood samples from the BEACON cohort.