Investigation of microbiome-host interactions in intestinal graft-versus-host disease as a clinical relevant condition of microbially triggered immune system modulation.

研究肠道移植物抗宿主病中微生物组与宿主相互作用作为微生物触发免疫系统调节的临床相关条件。

• 批准号: 320737172
• 负责人: Professor Dr. Christoph Karl Stein-Thöringer
• 金额: --
• 依托单位: Memorial Sloan Kettering Cancer Center
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/320737172?language=en
• 关键词: Investigation; microbiome; host; interactions; intestinal

Allogeneic hematopoietic stem-cell transplantation (allo HSCT) is an important immune-mediated therapy to cure people of life threatening hematological cancers and a variety of other diseases including autoimmune diseases. One of its major limitations is the life threatening complication of intestinal graft-versus-host disease (GVHD), an immunological reaction by the donor lymphocytes against the recipient causing severe inflammatory processes. The intestinal microbiota is a major modulator of gastrointestinal homeostasis and health. Now, there is increasing evidence that dysbiosis of the gut microbiota play a major role in the pathophysiology of GVHD. Clinically most relevant, it was demonstrated in independent clinical cohorts that a loss of microbial diversity and a shift in the composition of the intestinal microbiome predicts transplant-related mortality in allo HSCT patients. However, the mechanisms underlying the link between microbiota and GVHD are only marginally understood. For this reason, a research agenda is proposed to study basic principles of the interactions between the immune system, the intestines and the microbiota with the intestines. In detail, it is planned to pursue both a basic science and a translational, clinical approach. First, it is aimed to investigate mechanistically how changes in the gut microflora determine the occurrence of GVHD in transplanted patients focusing on bacterial genetics (16S RNA amplicon and metagenome sequencing), profiling of microbial metabolites and analyses of host immune parameters. In a further experimental approach, we plan to study the effects of microflora transfer from GHVD patients to germ-free mice in order to investigate its detailed contribution in inflammatory processes in the intestines. In a second aim targeted at the development of strategies to treat microbiota injury in GVHD, we will examine the effects of specific bacterial re-introduction on the intestinal flora and the action of specific microbial metabolites like short-chain fatty acids on GVHD in mouse models. In a third aim, it is planned to characterize the effects of antibiotics with different antimicrobial spectra to prevent intestinal dysbiosis and reduce GVHD-like processes in animal models. This research project will not only help to uncover important pathophysiological aspects of GVHD and thereby will promote the development of novel treatment strategies. Of note, it deals with fundamental questions of microbiome-host interaction and, especially, immune system regulation, and may therefore reveal general principles in the pathophysiology of inflammatory diseases.

异基因造血干细胞移植（allo HSCT）是一种重要的免疫介导疗法，用于治疗危及生命的血液系统癌症和包括自身免疫性疾病在内的各种其他疾病。其主要局限性之一是危及生命的肠移植物抗宿主病（GVHD）并发症，这是供体淋巴细胞对受体的免疫反应，引起严重的炎症过程。肠道微生物群是胃肠道稳态和健康的主要调节剂。现在，越来越多的证据表明，肠道微生物群的生态失调在GVHD的病理生理学中起着重要作用。临床上最相关的是，在独立的临床队列中证明，微生物多样性的丧失和肠道微生物组组成的变化预测了allo HSCT患者的移植相关死亡率。然而，微生物群和GVHD之间联系的潜在机制仅被边缘化。出于这个原因，提出了一个研究议程，以研究免疫系统，肠道和肠道微生物群之间相互作用的基本原理。详细地说，它计划追求基础科学和转化，临床方法。首先，它的目的是机械地研究肠道微生物菌群的变化如何决定移植患者中GVHD的发生，重点是细菌遗传学（16 S RNA扩增子和宏基因组测序），微生物代谢产物的分析和宿主免疫参数的分析。在进一步的实验方法中，我们计划研究从GHVD患者到无菌小鼠的微生物菌群转移的影响，以研究其在肠道炎症过程中的详细贡献。第二个目标是开发治疗GVHD中微生物群损伤的策略，我们将检查特定细菌重新引入对肠道植物群的影响以及特定微生物代谢产物（如短链脂肪酸）对GVHD的作用小鼠模型。在第三个目标中，计划表征具有不同抗菌谱的抗生素的作用，以防止肠道生态失调并减少动物模型中的GVHD样过程。该研究项目不仅有助于揭示GVHD的重要病理生理学方面，从而促进新治疗策略的发展。值得注意的是，它涉及微生物组-宿主相互作用的基本问题，特别是免疫系统调节，因此可能揭示炎性疾病病理生理学的一般原理。