Vedolizumab (VDZ) is a first-line treatment in ulcerative colitis (UC) that targets the α4β7- mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) axis. To determine the mechanisms of action of VDZ, we examined five distinct cohorts of patients with UC. A decrease in naïve B and T cells in the intestines and gut-homing (β7 + ) plasmablasts in circulation of VDZ-treated patients suggested that VDZ targets gut-associated lymphoid tissue (GALT). Anti-α4β7 blockade in wild-type and photoconvertible (KikGR) mice confirmed a loss of GALT size and cellularity because of impaired cellular entry. In VDZ-treated patients with UC, treatment responders demonstrated reduced intestinal lymphoid aggregate size and follicle organization and a reduction of β7 + IgG + plasmablasts in circulation, as well as IgG + plasma cells and FcγR-dependent signaling in the intestine. GALT targeting represents a previously unappreciated mechanism of action of α4β7-targeted therapies, with major implications for this therapeutic paradigm in UC.

中文翻译：

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肠道相关淋巴组织消耗与溃疡性结肠炎抗α4β7治疗的反应相关


维多珠单抗 (VDZ) 是溃疡性结肠炎 (UC) 的一线治疗药物，靶向 α4β7-粘膜血管地址素细胞粘附分子 1 (MAdCAM-1) 轴。为了确定 VDZ 的作用机制，我们检查了五个不同的 UC 患者队列。肠道中幼稚 B 细胞和 T 细胞的减少以及肠道归巢（β7 + ）接受 VDZ 治疗的患者循环中的浆母细胞表明 VDZ 靶向肠道相关淋巴组织 (GALT)。野生型和光转换 (KikGR) 小鼠中的抗 α4β7 阻断证实了由于细胞进入受损而导致 GALT 大小和细胞结构的损失。在接受 VDZ 治疗的 UC 患者中，治疗反应者表现出肠道淋巴聚集体大小和滤泡组织减少以及 β7 减少+免疫球蛋白G +循环中的浆母细胞以及 IgG +肠道中的浆细胞和 FcγR 依赖性信号传导。 GALT 靶向代表了 α4β7 靶向治疗的一种先前未被认识的作用机制，对 UC 的这种治疗范例具有重大意义。