Blockade of αEβ7 integrin suppresses accumulation of CD8+ and Th9 lymphocytes from patients with IBD in the inflamed gut in vivo
Blockade of αEβ7 integrin suppresses accumulation of CD8+ and Th9 lymphocytes from patients with IBD in the inflamed gut in vivo
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DOI：
10.1136/gutjnl-2016-312439
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发表时间：
2017-11-01
期刊：
影响因子：
24.5
通讯作者：
Neurath, Markus F.
中科院分区：
文献类型：
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作者：
Zundler, Sebastian;Schillinger, Daniela;Neurath, Markus F.
目的以淋巴细胞黏附为靶点的治疗方法与IBD的相关性越来越大。然而，抗黏附化合物作用的核心方面还不完全清楚。在炎症肠道的体内模型中，我们研究了α E β 7和α 4 β 7整合素的作用以及vedolizumab和etrolizumab对IBD T淋巴细胞运输的阻断作用。我们通过流式细胞术和免疫组织化学方法研究了整合素在IBD患者中的表达，同时在T细胞培养中研究了整合素的调控。整合素的功能相关性通过粘附试验和最近建立的人源化小鼠模型在右旋糖酐硫酸钠治疗的免疫缺陷小鼠中进行了评估。结果α - E - β 7在CD8（+）和CD4(+) Th9细胞中高表达，α - 4 - β 7在CD8+、Th2和Th17细胞中高表达。T细胞受体刺激和转化生长因子β是人T细胞α E β 7的主要诱导剂，而丁酸抑制α E β 7。与通过vedolizumab阻断α 4 β 7相比，通过etrolizumab替代抗体阻断β 7在3小时后显著降低体内CD8+和Th9细胞的结肠数量，而在0.5小时后没有发现差异。在接受维多单抗治疗的IBD患者的CD8+ T细胞上，AE β 7的表达更高。结论AE - β 7在体内与IBD CD8(+) T细胞和CD4(+) Th9细胞的肠道运输有关键关系，其主要作用可能是滞留。这些发现表明，除了α 4 β 7外，阻断α E β 7可能对CD8（+）和Th9细胞扩增的肠道疾病（如IBD）特别有效。
Objective Therapeutically targeting lymphocyte adhesion is of increasing relevance in IBD. Yet, central aspects of the action of antiadhesion compounds are incompletely understood. We investigated the role of alpha E beta 7 and alpha 4 beta 7 integrins and their blockade by vedolizumab and etrolizumab for trafficking of IBD T lymphocytes in an in vivo model of homing to and retention in the inflamed gut.Design We explored integrin expression in patients with IBD by flow cytometry and immunohistochemistry, while regulation of integrins was studied in T cell cultures. The functional relevance of integrins was assessed by adhesion assays and a recently established humanised mouse model in dextran sodium sulfate-treated immunodeficient mice.Results High expression of alpha E beta 7 was noted on CD8(+) and CD4(+) Th9 cells, while alpha 4 beta 7 was expressed on CD8+, Th2 and Th17 cells. T cell receptor stimulation and transforming growth factor beta were key inducers of alpha E beta 7 on human T cells, while butyric acid suppressed alpha E beta 7. In comparison to alpha 4 beta 7 blockade via vedolizumab, blockade of beta 7 via etrolizumab surrogate antibody superiorly reduced colonic numbers of CD8+ and Th9 cells in vivo after 3 hours, while no difference was noted after 0.5 hours. AE beta 7 expression was higher on CD8+ T cells from patients with IBD under vedolizumab therapy.Conclusions AE beta 7 is of key relevance for gut trafficking of IBD CD8(+) T cells and CD4(+) Th9 cells in vivo and mainly retention might account for this effect. These findings indicate that blockade of alpha E beta 7 in addition to alpha 4 beta 7 may be particularly effective in intestinal disorders with expansion of CD8(+) and Th9 cells such as IBD.