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

L Schwab, L Goroncy, S Palaniyandi, S Gautam… - Nature medicine, 2014 - nature.com
L Schwab, L Goroncy, S Palaniyandi, S Gautam, A Triantafyllopoulou, A Mocsai
Nature medicine, 2014nature.com
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 …
Abstract
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 Bcl-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.
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