title: Emergency granulopoiesis promotes neutrophil-dendritic cell encounters that prevent mouse lung allograft acceptance.
abstract: The mechanisms by which innate immune signals regulate alloimmune responses remain poorly understood. In the present study, we show by intravital 2-photon microscopy direct interactions between graft-infiltrating neutrophils and donor CD11c(+) dendritic cells (DCs) within orthotopic lung allografts immediately after reperfusion. Neutrophils isolated from the airways of lung transplantation recipients stimulate donor DCs in a contact-dependent fashion to augment their production of IL-12 and expand alloantigen-specific IFN-γ(+) T cells. DC IL-12 expression is largely regulated by degranulation and induced by TNF-α associated with the neutrophil plasma membrane. Extended cold ischemic graft storage enhances G-CSF-mediated granulopoiesis and neutrophil graft infiltration, resulting in exacerbation of ischemia-reperfusion injury after lung transplantation. Ischemia reperfusion injury prevents immunosuppression-mediated acceptance of mouse lung allografts unless G-CSF-mediated granulopoiesis is inhibited. Our findings identify granulopoiesis-mediated augmentation of alloimmunity as a novel link between innate and adaptive immune responses after organ transplantation.
authors.affiliation: Department of Surgery, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kreisel
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Sugimoto
authors.forename: Jihong
authors.initials: J
authors.lastname: Zhu
authors.forename: Ruben
authors.initials: R
authors.lastname: Nava
authors.forename: Wenjun
authors.initials: W
authors.lastname: Li
authors.forename: Mikio
authors.initials: M
authors.lastname: Okazaki
authors.forename: Sumiharu
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Mohsen
authors.initials: M
authors.lastname: Ibrahim
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Huang
authors.forename: Kelsey A
authors.initials: KA
authors.lastname: Toth
authors.forename: Jon H
authors.initials: JH
authors.lastname: Ritter
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Krupnick
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Miller
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Gelman
mesh_terms: D000208:Acute Disease; D000818:Animals; D015550:Cell Degranulation / Q000276:immunology; D002462:Cell Membrane / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D018664:Interleukin-12 / Q000378:metabolism; D019891:Leukopoiesis / Q000187:drug effects / Q000276:immunology*; D016040:Lung Transplantation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D015427:Reperfusion Injury / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D014181:Transplantation Immunology / Q000276:immunology; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; D018664:Interleukin-12