Department of General, Visceral und Transplantation Surgery, Hospital of the Ludwig Maximilian University of Munich, München, Germany.
Institute of Laboratory Medicine, Hospital of the Ludwig Maximilian University of Munich, München, Germany.
Inflamm Bowel Dis. 2020 Mar 4;26(4):557-569. doi: 10.1093/ibd/izz284.
To date, responsiveness to tumor necrosis factor alpha inhibitors in ulcerative colitis (UC) patients is not predictable. This is partially due to a lack of understanding of the underlying inflammatory processes. The aim of this study was to identify immunological subgroups of patients with UC and to test responsiveness to adalimumab in these subgroups in the mouse model of ulcerative colitis (UC), which is based on NOD/scid IL-2Rγ null (NSG) mice reconstituted with peripheral blood mononuclear cells (PBMCs; NSG-UC).
The immunological profiles of 40 UC patients and 16 non-UC donors were determined by flow cytometric analysis of PBMCs in a snapshot and longitudinal study and analyzed by principal component, orthogonal partial least square discrimination (oPLS-DA), and hierarchical clustering analysis. NSG mice were reconstituted 5 times at consecutive time points with PBMCs from a single donor and were analyzed for frequencies of human leukocytes and histological phenotype. The response to adalimumab of 2 identified subgroups was tested in the NSG-UC model. We used the clinical, colon, and histological score, serum levels of glutamic and aspartic acid, and IL-6 and IL-1ß. Response was analyzed by oPLS-DA.
Analysis revealed a distinction between UC and non-UC donors. Hierarchical clustering identified 2 major subgroups in UC patients. Group I was characterized by TH17 and M1 monocytes, group II by TH2/TH1, and switched B cells. These subgroups reflect the dynamics of inflammation as patients. NSG-UC mice achieved an immunological phenotype reflecting the patient's immunological phenotype. oPLS-DA revealed that NSG-UC mice reconstituted with PBMCs from group II responded better to adalimumab.
The combination of profiling and testing of therapeutics in the NSG-UC model may lead to individualized and phase-dependent therapies.
迄今为止，肿瘤坏死因子-α抑制剂在溃疡性结肠炎（UC）患者中的反应性尚不可预测。这部分是由于对潜在炎症过程缺乏了解。本研究的目的是确定 UC 患者的免疫学亚群，并在基于 NOD/scid IL-2Rγnull（NSG）小鼠的溃疡性结肠炎（UC）小鼠模型中测试这些亚群对阿达木单抗的反应性，该模型是用外周血单核细胞（PBMC；NSG-UC）重建的。
通过对 PBMC 的流式细胞术分析，在快照和纵向研究中确定了 40 名 UC 患者和 16 名非 UC 供体的免疫特征，并通过主成分分析、正交偏最小二乘判别（oPLS-DA）和层次聚类分析进行分析。连续 5 次用来自单个供体的 PBMC 重建 NSG 小鼠，并分析人白细胞和组织表型的频率。在 NSG-UC 模型中测试了 2 个鉴定亚群对阿达木单抗的反应。我们使用临床、结肠和组织学评分、谷氨酸和天冬氨酸的血清水平以及 IL-6 和 IL-1β。通过 oPLS-DA 进行反应分析。
分析显示 UC 和非 UC 供体之间存在区别。层次聚类在 UC 患者中确定了 2 个主要亚群。第 I 组的特征是 TH17 和 M1 单核细胞，第 II 组的特征是 TH2/TH1 和转换 B 细胞。这些亚群反映了患者炎症的动态变化。NSG-UC 小鼠获得了反映患者免疫表型的免疫表型。oPLS-DA 显示，用来自第 II 组的 PBMC 重建的 NSG-UC 小鼠对阿达木单抗的反应更好。
在 NSG-UC 模型中进行分析和测试治疗方法的组合可能会导致个体化和阶段依赖性治疗。
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