Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage

作者：Schwab Lukas; Goroncy Luise; Palaniyandi Senthilnathan; Gautam Sanjivan; Triantafyllopoulou Antigoni; Mocsai Attila; Reichardt Wilfried; Karlsson Fridrik J; Radhakrishnan Sabarinath V; Hanke Kathrin; Schmitt Graeff Annette; Freudenberg Marina; von Loewenich Friederike D; Wolf Philipp; Leonhardt Franziska; Baxan Nicoleta; Pfeifer Dietmar; Schmah Oliver; Schoenle Anne; Martin Stefan F; Mertelsmann Roland; Duyster Justus; Finke Juergen; Prinz Marco; Henneke Philipp

来源：Nature Medicine, 2014, 20(6): 648-654.

DOI：10.1038/nm.3517

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.

• 出版日期2014-6