CD39-dependent regulation of innate immune responses and modulation of exacerbated sterile inflammation in acute-on-chronic liver failure

CD39依赖性调节先天免疫反应和慢性肝衰竭急性加重无菌性炎症的调节

• 批准号: 299534341
• 负责人: Professor Dr. Moritz Schmelzle
• 金额: --
• 依托单位: Klinik für Allgemein-, Viszeral- und Transplantationschirurgie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/299534341?language=en
• 关键词: CD39; dependent; regulation; innate; immune

Acute on chronic liver failure (ACLF) is defined as an acute hepatic insult in patients with chronic liver disease and is characterized by high death rates. Systemic inflammation is considered a hallmark of ACLF and can be linked to progression of liver failure and clinical deterioration. Criteria for ACLF and the systemic inflammatory response syndrome (SIRS) substantially overlap and support the assumption of mechanistic similarities between both syndromes. Thus, modulating inflammation and the linked immune responses in ACLF might help to restore homeostasis and improve of regenerative capacities of the injured liver.We hypothesize that the catalyzed hydrolysis of purinergic damage-associated molecular patterns (DAMPS), such as extracellular ATP, by the ectonucleotidase CD39 is crucially involved in the regulation of innate immune responses and the modulation of exacerbated sterile inflammation in ACLF. We here aim to describe characteristics and functions of monocyte subsets in ACLF and to investigate implications of purinergic signaling. We further plan to investigate the therapeutical relevance of non-classical monocytes and the immune-type ectonucleotidase CD39 in experimental ACLF. Finally, we will evaluate the clinical significance of cellular and non-cellular immune responses in ACLF patients enrolled in the GRAFT Trial.

急性慢性肝功能衰竭(ACLF)是慢性肝病患者的一种急性肝功能损害，以高死亡率为特征。全身性炎症被认为是ACLF的一个标志，并可能与肝功能衰竭的进展和临床恶化有关。ACLF和全身性炎症反应综合征(SIRS)的标准有很大的重叠，并支持两种综合征在机制上相似的假设。因此，调节ACLF的炎症反应和相关的免疫反应可能有助于恢复受损肝脏的动态平衡和提高再生能力。我们推测，CD39催化的胞外ATP等嘌呤能损伤相关分子模式(DAMP)的水解在ACLF的先天性免疫反应的调节和加重的不孕症炎症的调节中起着至关重要的作用。我们在这里的目的是描述ACLF中单核细胞亚群的特征和功能，并探讨嘌呤能信号转导的意义。我们进一步计划研究非经典单核细胞与免疫型ECN酶CD39在实验性ACLF中的治疗相关性。最后，我们将评估参加移植物试验的ACLF患者的细胞和非细胞免疫反应的临床意义。