The role of intestinal antimicrobial and inflammatory molecules in acute graft-versus-host disease

肠道抗菌和炎症分子在急性移植物抗宿主病中的作用

• 批准号: 380033355
• 负责人: Professor Dr. Robert Zeiser
• 金额: --
• 依托单位: Klinik für Innere Medizin I - Hämatologie, Onkologie und Stammzelltransplantation
• 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/380033355?language=en
• 关键词: role; intestinal; antimicrobial; inflammatory; molecules

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative therapy for different hematological malignancies. Acute graft-versus-host disease (aGVHD), relapse and infections are the major life-threatening complications after allo-HCT. We reported that activation of the innate immune system, in particular neutrophil granulocytes (neutrophils), is an early step in the pathogenesis of aGVHD. Neutrophil migration and MHC-II expression were reduced by JAK1/2 inhibition. Our previous work had shown that JAK1/2 inhibition reduced aGVHD in mice and in patients, proven by a multicenter phase III trial. While neutrophils that occurred in the early phase after allo-HCT were pro-inflammatory, our preliminary data indicate that neutrophils that occur in the lamina propria of mice with healing GVHD may promote tissue repair and reduce inflammation. Using single cell RNA sequencing on neutrophils residing in the intestinal tract at late time points after allo-HCT when GVHD is healing, we identified multiple antimicrobial and inflammatory molecules in neutrophils including the antimicrobial glycoprotein Lipocalin-2 (LCN2), that is known to limit bacterial growth. Our preliminary data indicate that LCN2 treatment reduced GVHD-related mortality and macrophages exposed to LCN2 produced multiple molecules that reduce T cell activation including arginase-1. In this proposal we plan to determine the role of LCN2 for the healing process in late acute GVHD. A particular focus will be on the regulation of inflammatory, antimicrobial and immunosuppressive molecules production, induced via LCN2 in intestinal macrophages. We hypothesize that LCN2-induced arginase-1 production reduces allo-reactive T cell activation in the intestines, thereby allowing the epithelium to heal. Additionally we wish to evaluate the impact of LCN2 on the intestinal microbiome composition, on metabolic activity of donor T cells and on graft-versus-leukemia effects. To clarify if the results from the murine setting can be transferred into the human situation, we will determine the level of LCN2 in different cell types residing in human intestinal tissues with or without active GVHD and healing GVHD. Additionally we will analyze the tissues for LCN2, arginase-1 and 24p3R / SLC22A17 in patients undergoing allo-HCT with the prospect to clarify if these correlate with SR-GVHD and non-relapse mortality. Overall this project aims at determining the role of LCN2 and other antimicrobial and inflammatory molecules in GVHD to better understand the GVHD healing process and to develop potential novel treatments for patients with GVHD.

异基因造血细胞移植（allo-HCT）是治疗各种恶性血液病的有效方法。急性移植物抗宿主病（aGVHD）、复发和感染是allo-HCT后危及生命的主要并发症。我们报道了先天免疫系统的激活，特别是中性粒细胞（中性粒细胞），是aGVHD发病机制的早期步骤。JAK 1/2抑制可降低神经元迁移和MHC-II表达。我们之前的工作已经表明，JAK 1/2抑制减少了小鼠和患者的aGVHD，这一点已被多中心III期试验所证实。虽然在allo-HCT后早期出现的中性粒细胞是促炎性的，但我们的初步数据表明，在具有愈合GVHD的小鼠的固有层中出现的中性粒细胞可以促进组织修复并减少炎症。当GVHD正在愈合时，在allo-HCT后的晚期时间点对驻留在肠道中的中性粒细胞进行单细胞RNA测序，我们鉴定了中性粒细胞中的多种抗菌和炎症分子，包括已知限制细菌生长的抗菌糖蛋白Lipocalin-2（LCN 2）。我们的初步数据表明，LCN 2治疗降低了GVHD相关的死亡率，暴露于LCN 2的巨噬细胞产生了多种减少T细胞活化的分子，包括T细胞活化酶-1。在这项提案中，我们计划确定LCN 2在晚期急性GVHD愈合过程中的作用。一个特别的重点将是炎症，抗菌和免疫抑制分子的生产，诱导通过LCN 2在肠道巨噬细胞的调节。我们假设LCN 2诱导的抗氧化酶-1的产生减少了肠道中的同种异体反应性T细胞活化，从而使上皮愈合。此外，我们希望评估LCN 2对肠道微生物组组成、供体T细胞代谢活性和移植物抗白血病效应的影响。为了阐明来自小鼠环境的结果是否可以转移到人类情况中，我们将确定存在于有或没有活动性GVHD和愈合性GVHD的人肠组织中的不同细胞类型中的LCN 2水平。此外，我们将分析接受allo-HCT的患者的组织中的LCN 2、LCN酶-1和24 p3 R/SLC 22 A17，前景是澄清这些是否与SR-GVHD和非复发死亡率相关。总的来说，该项目旨在确定LCN 2和其他抗菌和炎症分子在GVHD中的作用，以更好地了解GVHD愈合过程，并为GVHD患者开发潜在的新型治疗方法。