On the pathophysiology of Enterococcus as intestinal commensal in the development of gut graft-versus-host disease

肠球菌作为肠道共生菌在肠道移植物抗宿主病发展中的病理生理学

• 批准号: 449426712
• 负责人: Professor Dr. Christoph Karl Stein-Thöringer
• 金额: --
• 依托单位: Innere Medizin I: Gastroenterologie, Hepatologie, Infektionskrankheiten
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/449426712?language=en
• 关键词: pathophysiology; Enterococcus; intestinal; commensal; development

Allogeneic hematopoetic cell transplantation (allo-HCT) is an important, curative-intend immunotherapy for hematological malignancies, but it carries severe toxicities such as graft-versus-host disease (GVHD) or risk for infections. We recently demonstrated in patients and mouse models that the intestinal commensal Enterococcus plays a major role in mediating these toxicities after allo-HCT. The proposed research program will focus on the interaction network of host – microbiota – enterococci as pathogens. It will allow us to unravel the exact pathomechanisms by which Enterococcus exacerbates acute GVHD. We hypothesise and test whether this occurs either through the stimulation of host antigen-presenting and dendritic cells, the expansion of alloreactive T cells, and a disruption of intestinal barriers. As all these factors have not been explored so far, this grant application proposes a series of in vitro studies and experiments in animal models to elucidate these fatal microbe-immune interactions. In perspective, this research project will help us to define novel targets against Enterococcus-induced host toxicities for the benefit of several patient cohorts that are at risk for Enterococcus infections.

异基因造血细胞移植（allo-HCT）是治疗血液恶性肿瘤的一种重要的、具有治愈性的免疫疗法，但它具有严重的毒性，例如移植物抗宿主病（GVHD）或感染风险。我们最近在患者和小鼠模型中证明，肠道共生肠球菌在介导异基因 HCT 后的这些毒性中发挥着重要作用。拟议的研究计划将重点关注宿主 - 微生物群 - 作为病原体的肠球菌之间的相互作用网络。它将使我们能够揭示肠球菌加剧急性 GVHD 的确切病理机制。我们假设并测试这种情况是否通过刺激宿主抗原呈递细胞和树突状细胞、同种异体反应性 T 细胞的扩增以及肠道屏障的破坏而发生。由于迄今为止所有这些因素尚未得到探索，本拨款申请提出了一系列动物模型体外研究和实验，以阐明这些致命的微生物-免疫相互作用。从长远来看，该研究项目将帮助我们确定针对肠球菌引起的宿主毒性的新靶标，以造福于几个面临肠球菌感染风险的患者群体。