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

急性慢性肝功能衰竭（ACLF）被定义为慢性肝病患者的急性肝损伤，其特点是死亡率高。全身性炎症被认为是ACLF的标志，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，这支持了两种综合征在机制上相似的假设。因此，在ACLF中调节炎症和相关的免疫反应可能有助于恢复体内平衡和提高损伤肝脏的再生能力。我们假设，嘌呤能损伤相关分子模式（DAMPS），如细胞外ATP，被外核苷酶CD39催化水解，在ACLF先天免疫反应的调节和无菌炎症加剧的调节中起着至关重要的作用。我们的目的是描述ACLF中单核细胞亚群的特征和功能，并研究嘌呤能信号的含义。我们计划进一步研究非经典单核细胞和免疫型外核苷酶CD39在实验性ACLF中的治疗相关性。最后，我们将评估参与GRAFT试验的ACLF患者的细胞和非细胞免疫反应的临床意义。

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.