Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage
Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage
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DOI：
10.1038/nm.3517
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发表时间：
2014-06-01
期刊：
影响因子：
82.9
通讯作者：
Zeiser, Robert
中科院分区：
文献类型：
--
作者：
Schwab, Lukas;Goroncy, Luise;Zeiser, Robert
急性移植物抗宿主病（GVHD）极大地限制了异基因造血细胞移植（allo-HCT）的广泛应用。抗原呈递细胞和T细胞是通常与GVHD发病机制相关的群体。值得注意的是，中性粒细胞是最大的人类白色血细胞群体。细胞裂解趋化因子并产生活性氧，从而促进T细胞活化（1，2）。因此，在同种异体免疫应答期间，中性粒细胞可以放大由预处理方案引起的组织损伤。我们通过体内髓过氧化物酶成像分析了allo-HCT后小鼠回肠的中性粒细胞浸润，发现浸润水平取决于局部微生物植物群，在无菌条件下无法检测到。中性粒细胞的物理或遗传耗竭降低了GVHD相关的死亡率。中性粒细胞对GVHD严重性的贡献需要活性氧（ROS），因为中性粒细胞中的选择性Cybb（编码细胞色素B-245，β多肽，也称为NOX 2）缺陷损害ROS产生导致较低水平的组织损伤、GVHD相关死亡率和效应表型T细胞。BcI-xL转基因中性粒细胞存活率的提高增加了GVHD的严重程度。相比之下，当我们将缺乏Toll样受体-2（TLR 2）、TLR 3、TLR 4、TLR 7和TLR 9的中性粒细胞（这些细胞通常不太被易位细菌激活）转移到野生型C57 BL/6小鼠中时，GVHD严重程度降低。在人类中，肠道GVHD的严重程度与GVHD病变中存在的中性粒细胞水平密切相关。这项研究描述了一个新的潜在作用，中性粒细胞在小鼠和人类GVHD的发病机制。
Acute graft-versus-host disease (GVHD) considerably limits wider usage of allogeneic hematopoietic cell transplantation (allo-HCT). Antigen-presenting cells and T cells are populations customarily associated with GVHD pathogenesis. Of note, neutrophils are the largest human white blood cell population. The cells cleave chemokines and produce reactive oxygen species, thereby promoting T cell activation(1,2). Therefore, during an allogeneic immune response, neutrophils could amplify tissue damage caused by conditioning regimens. We analyzed neutrophil infiltration of the mouse ileum after allo-HCT by in vivo myeloperoxidase imaging and found that infiltration levels were dependent on the local microbial flora and were not detectable under germ-free conditions. Physical or genetic depletion of neutrophils reduced GVHD-related mortality. The contribution of neutrophils to GVHD severity required reactive oxygen species (ROS) because selective Cybb (encoding cytochrome b-245, beta polypeptide, also known as NOX2) deficiency in neutrophils impairing ROS production led to lower levels of tissue damage, GVHD-related mortality and effector phenotype T cells. Enhanced survival of BcI-xL transgenic neutrophils increased GVHD severity. In contrast, when we transferred neutrophils lacking Toll-like receptor-2 (TLR2), TLR3, TLR4, TLR7 and TLR9, which are normally less strongly activated by translocating bacteria, into wild-type C57BL/6 mice, GVHD severity was reduced. In humans, severity of intestinal GVHD strongly correlated with levels of neutrophils present in GVHD lesions. This study describes a new potential role for neutrophils in the pathogenesis of GVHD in both mice and humans.