Gut-associated lymphoid tissue attrition associates with response to anti-α4β7 therapy in ulcerative colitis.
Gut-associated lymphoid tissue attrition associates with response to anti-α4β7 therapy in ulcerative colitis.
复制标题
肠道相关淋巴组织磨损与溃疡性结肠炎抗α4β7 治疗的反应相关。
DOI：
10.1101/2023.01.19.524731
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Tankelevich,M
中科院分区：
文献类型：
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作者：
Canales-Herrerias,Pablo;Uzzan,Mathieu;Seki,Akihiro;Czepielewski,RafaelS;Verstockt,Bram;Livanos,Alexandra;Raso,Fiona;Dunn,Alexandra;Dai,Daniel;Wang,Andrew;Al-Taie,Zainab;Martin,Jerome;Ko,HuaibinM;Tokuyama,Minami;Tankelevich,M
Vedolizumab （VDZ）是溃疡性结肠炎（UC）的一线治疗药物，靶向α4β7-粘膜血管寻址蛋白细胞粘附分子1 （MAdCAM-1）轴。为了确定VDZ的作用机制，我们检查了五组不同的UC患者。VDZ治疗患者肠道中naïve B细胞和T细胞以及循环中肠归巢（β7+）浆母细胞的减少表明VDZ靶向肠道相关淋巴组织（GALT）。野生型和光转化型（KikGR）小鼠的抗α4β7阻断证实，由于细胞进入受损，GALT大小和细胞性丧失。在vdz治疗的UC患者中，治疗应答者表现出肠道淋巴细胞聚集大小和卵泡组织减少，循环中β7+IgG+浆母细胞减少，以及肠道中IgG+浆细胞和fc γ r依赖信号的减少。GALT靶向代表了α4β7靶向治疗的一种以前未被认识的作用机制，对UC的这种治疗模式具有重要意义。
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.