Intestinal tissue-resident memory T cells as mediators of inflammatory bowel disease and possible targets of etrolizumab therapy

肠道组织驻留记忆 T 细胞作为炎症性肠病的介质和 etrolizumab 治疗的可能靶点

• 批准号: 356486795
• 负责人: Professor Dr. Sebastian Zundler
• 金额: --
• 依托单位: Medizinische Klinik 1 - Gastroenterologie, Pneumologie und Endokrinologie
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/356486795?language=en
• 关键词: Intestinal; tissue; resident; memory; cells

Inflammatory bowel diseases (IBD) comprise Crohn's disease (CD) and ulcerative colitis (UC). They are characterized by chronic relapsing inflammation of the intestinal tract and cause considerable morbidity. Treatment options are still insufficient and the precise pathogenesis is still not clear. However, it is commonly accepted that among other factors the intestinal immune system and especially T cells are crucial mediators of the diseases. They are recruited to the inflamed intestine in a highly complex process involving activation and priming, recirculation and so called homing. A whole variety of different T cell subpopulations with different functions and tasks is known. One of these is the recently described population of tissue-resident memory T cells (TRM cells), which resides in mucosal tissues in close contact to the epithelium without re-circulating and thus establishes immediate immunological memory in peripheral tissues. In the gut, these cells are characterized by expression of alphaEbeta7 integrin and CD69 and Hobit has been recently identified as an important transcriptional regulator of TRM cell differentiation. Although evidence from other models and diseases suggests a crucial role of TRM cells in immunologically mediated diseases, their function in IBD has not yet been addressed. Moreover, own data strongly support the notion that the drug etrolizumab (an anti-beta7 antibody) currently investigated in advanced clinical trials might interfere with tissue residency of TRM cells. Thus, the central hypothesis of this proposal is that TRM cells are crucial mediators of recurrent inflammatory flares in IBD and that the upcoming therapeutic agent etrolizumab might interfere with these cells. This hypothesis will be addressed by taking advantage of Hobit x Blimp-1 double knockout and CD69 knockout mice in both acute and chronic dextran sodium sulphate (DSS) colitis as well as in T cell transfer colitis models. Furthermore, the role of etrolizumab will be deciphered in vitro and in vivo in animal models and with intravital confocal microscopy. A potential role of pathogen-specific TRM cells in the mediation of acute inflammatory flare will be assessed in murine models and, finally, experiments in samples from IBD patients with or without etrolizumab therapy will reveal the importance of TRM cells in human IBD.

炎症性肠病（IBD）包括克罗恩病（CD）和溃疡性结肠炎（UC）。它们的特征是慢性复发性肠道炎症，并导致相当大的发病率。治疗选择仍然不足，确切的发病机制仍然不清楚。然而，人们普遍认为，在其他因素中，肠道免疫系统，特别是T细胞是疾病的关键介质。它们在一个高度复杂的过程中被招募到发炎的肠道，这个过程涉及激活和启动、再循环和所谓的归巢。已知具有不同功能和任务的各种不同T细胞亚群。其中之一是最近描述的组织驻留记忆T细胞（TRM细胞）群体，其驻留在粘膜组织中与上皮紧密接触而不再循环，从而在外周组织中建立即时免疫记忆。在肠道中，这些细胞的特征在于表达α Ebeta 7整联蛋白和CD 69，Hobit最近被鉴定为TRM细胞分化的重要转录调节因子。尽管来自其他模型和疾病的证据表明TRM细胞在免疫介导的疾病中起着至关重要的作用，但它们在IBD中的功能尚未得到解决。此外，我们的数据强烈支持目前在高级临床试验中研究的药物etrolizumab（一种抗β 7抗体）可能会干扰TRM细胞的组织驻留的观点。因此，该提议的中心假设是TRM细胞是IBD中复发性炎症发作的关键介质，并且即将到来的治疗剂etrolizumab可能会干扰这些细胞。这一假设将通过在急性和慢性葡聚糖硫酸钠（DSS）结肠炎以及T细胞转移结肠炎模型中利用Hobit x Blimp-1双敲除和CD 69敲除小鼠来解决。此外，etrolizumab的作用将在体外和体内的动物模型和活体共聚焦显微镜破译。将在鼠模型中评估病原体特异性TRM细胞在急性炎症发作介导中的潜在作用，并且最后，在来自有或没有etrolizumab治疗的IBD患者的样品中的实验将揭示TRM细胞在人IBD中的重要性。

项目成果

Hobit- and Blimp-1-driven CD4+ tissue-resident memory T cells control chronic intestinal inflammation

• DOI: 10.1038/s41590-018-0298-5
• 发表时间: 2019-01
• 期刊: Nature Immunology
• 影响因子: 30.5
• 作者: S. Zundler;E. Becker;M. Spocinska;Monique Slawik;Loreto Parga-Vidal;Regina Stark;Maximilian Wiendl;R. Atreya;T. Rath;M. Leppkes;K. Hildner;R. López-Posadas;S. Lukassen;A. Ekici;C. Neufert;I. Atreya;K. V. van Gisbergen;M. Neurath

Three-Dimensional Cross-Sectional Light-Sheet Microscopy Imaging of the Inflamed Mouse Gut.

• DOI: 10.1053/j.gastro.2017.07.022
• 发表时间: 2017-09
• 期刊: Gastroenterology
• 影响因子: 29.4
• 作者: S. Zundler;Anika Klingberg;D. Schillinger;S. Fischer;C. Neufert;I. Atreya;M. Gunzer;M. Neurath