Multimodal Profiling of Peripheral Blood Identifies Proliferating Circulating Effector CD4+ T Cells as Predictors for Response to Integrin α4β7-Blocking Therapy in Inflammatory Bowel Disease.

IF 25.7 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Gastroenterology Pub Date : 2024-09-28 DOI:10.1053/j.gastro.2024.09.021
Veronika Horn, Camila A Cancino, Lisa Maria Steinheuer, Benedikt Obermayer, Konstantin Fritz, Anke L Nguyen, Kim Susan Juhran, Christina Plattner, Diana Bösel, Lotte Oldenburg, Marie Burns, Axel Ronald Schulz, Mariia Saliutina, Eleni Mantzivi, Donata Lissner, Thomas Conrad, Mir-Farzin Mashreghi, Sebastian Zundler, Elena Sonnenberg, Michael Schumann, Lea-Maxie Haag, Dieter Beule, Lukas Flatz, Zlatko Trjanoski, Geert D'Haens, Carl Weidinger, Henrik E Mei, Britta Siegmund, Kevin Thurley, Ahmed N Hegazy
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Abstract

Background & aims: Despite the success of biological therapies in treating inflammatory bowel disease, managing patients remains challenging due to the absence of reliable predictors of therapy response.

Methods: In this study, we prospectively sampled 2 cohorts of patients with inflammatory bowel disease receiving the anti-integrin α4β7 antibody vedolizumab. Samples were subjected to mass cytometry; single-cell RNA sequencing; single-cell variable, diversity, and joining sequencing; serum proteomics; and multidimensional flow cytometry to comprehensively assess vedolizumab-induced immunologic changes in the peripheral blood and their potential associations with treatment response.

Results: Vedolizumab treatment led to substantial alterations in the abundance of circulating immune cell lineages and modified the T-cell receptor diversity of gut-homing CD4+ memory T cells. Through integration of multimodal parameters and machine learning, we identified a significant increase in proliferating CD4+ memory T cells among nonresponders before treatment compared with responders. This predictive T-cell signature demonstrated an activated T-helper 1/T-helper 17 cell phenotype and exhibited elevated levels of integrin α4β1, potentially making these cells less susceptible to direct targeting by vedolizumab.

Conclusions: These findings provide a reliable predictive classifier with significant implications for personalized inflammatory bowel disease management.

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外周血多模态分析确定增殖的循环效应CD4+T细胞是炎症性肠病患者对整合素α4β7阻断疗法反应的预测因子。
背景与目的尽管生物疗法在治疗炎症性肠病(IBD)方面取得了成功,但由于缺乏可靠的治疗反应预测指标,患者管理仍面临挑战:在这项研究中,我们对接受抗整合素α4β7抗体维多珠单抗治疗的两组IBD患者进行了前瞻性采样。对样本进行了质谱、单细胞RNA测序、单细胞V(D)J测序、血清蛋白质组学和多维流式细胞仪检测,以全面评估维多珠单抗诱导的外周血免疫学变化及其与治疗反应的潜在关联:结果:维多利珠单抗治疗导致循环免疫细胞系的丰度发生重大变化,并改变了肠道归巢CD4+记忆T细胞的T细胞受体多样性。通过整合多模态参数和机器学习,我们发现与应答者相比,治疗前非应答者增殖的 CD4+ 记忆 T 细胞显著增加。这种预测性T细胞特征显示出活化的Th1/Th17表型,并表现出整合素α4β1水平的升高,这可能使这些细胞不易被韦多珠单抗直接靶向:这些发现提供了一个可靠的预测分类器,对个性化 IBD 管理具有重要意义。
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来源期刊
Gastroenterology
Gastroenterology 医学-胃肠肝病学
CiteScore
45.60
自引率
2.40%
发文量
4366
审稿时长
26 days
期刊介绍: Gastroenterology is the most prominent journal in the field of gastrointestinal disease. It is the flagship journal of the American Gastroenterological Association and delivers authoritative coverage of clinical, translational, and basic studies of all aspects of the digestive system, including the liver and pancreas, as well as nutrition. Some regular features of Gastroenterology include original research studies by leading authorities, comprehensive reviews and perspectives on important topics in adult and pediatric gastroenterology and hepatology. The journal also includes features such as editorials, correspondence, and commentaries, as well as special sections like "Mentoring, Education and Training Corner," "Diversity, Equity and Inclusion in GI," "Gastro Digest," "Gastro Curbside Consult," and "Gastro Grand Rounds." Gastroenterology also provides digital media materials such as videos and "GI Rapid Reel" animations. It is abstracted and indexed in various databases including Scopus, Biological Abstracts, Current Contents, Embase, Nutrition Abstracts, Chemical Abstracts, Current Awareness in Biological Sciences, PubMed/Medline, and the Science Citation Index.
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