Vedolizumab is associated with changes in innate rather than adaptive immunity in patients with inflammatory bowel disease
Vedolizumab is associated with changes in innate rather than adaptive immunity in patients with inflammatory bowel disease
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DOI：
10.1136/gutjnl-2018-316023
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发表时间：
2019-01-01
期刊：
影响因子：
24.5
通讯作者：
Schreiber, Stefan
中科院分区：
文献类型：
--
作者：
Zeissig, Sebastian;Rosati, Elisa;Schreiber, Stefan
Vedolizumab是一种针对整合素异二聚体α 4 β 7的单克隆抗体，已被批准用于治疗克罗恩病和溃疡性结肠炎。vedolizumab的疗效被认为是由于抑制肠道T细胞运输，尽管支持这一结论的人体数据很少。因此，我们在炎症性肠病（IBD）患者中使用抗炎治疗TNF α抗体英夫利昔单抗作为对照，对vedolizumab诱导的粘膜和全身免疫改变进行了全面分析。设计I免疫表型、免疫组织化学、T细胞受体谱和RNA测序是通过对IBD患者在使用vedolizumab （n=18）或抗tnf α抗体英夫利昔单抗（n=20）治疗前和治疗期间的血液和结肠活检进行的。使用单光子发射计算机断层扫描和子宫内膜显微镜评估体内白细胞运输。结果Vedolizumab与固有层T细胞的丰度或表型改变无关，也不影响粘膜T细胞库或体内白细胞运输。然而，令人惊讶的是，α 4 β 7抗体治疗与先天免疫的实质性影响相关，包括巨噬细胞群体的变化和参与微生物感知、化学吸引和先天效应反应调节的分子表达的显著改变。这些作用是韦多单抗所特有的，在TNF α抗体英夫利昔单抗中没有观察到，并且与肠道炎症的抑制有关。结论本研究提示，调节先天免疫有助于维多单抗治疗IBD的疗效。
Objective Vedolizumab, a monoclonal antibody directed against the integrin heterodimer alpha 4 beta 7, is approved for the treatment of Crohn's disease and ulcerative colitis. The efficacy of vedolizumab has been suggested to result from inhibition of intestinal T cell trafficking although human data to support this conclusion are scarce. We therefore performed a comprehensive analysis of vedolizumab-induced alterations in mucosal and systemic immunity in patients with inflammatory bowel disease (IBD), using antiinflammatory therapy with the TNF alpha antibody infliximab as control.Design I mmunophenotyping, immunohistochemistry, T cell receptor profiling and RNA sequencing were performed using blood and colonic biopsies from patients with IBD before and during treatment with vedolizumab (n=18) or, as control, the anti-TNF alpha antibody infliximab (n=20). Leucocyte trafficking in vivo was assessed using single photon emission computed tomography and endomicroscopy.Results Vedolizumab was not associated with alterations in the abundance or phenotype of lamina propria T cells and did not affect the mucosal T cell repertoire or leucocyte trafficking in vivo. Surprisingly, however, alpha 4 beta 7 antibody treatment was associated with substantial effects on innate immunity including changes in macrophage populations and pronounced alterations in the expression of molecules involved in microbial sensing, chemoattraction and regulation of the innate effector response. These effects were specific to vedolizumab, not observed in response to the TNF alpha antibody infliximab, and associated with inhibition of intestinal inflammation.Conclusion Our findings suggest that modulation of innate immunity contributes to the therapeutic efficacy of vedolizumab in IBD.