title: Lung parenchyma-derived IL-6 promotes IL-17A-dependent acute lung injury after allogeneic stem cell transplantation.
abstract: Idiopathic pneumonia syndrome (IPS) is a relatively common, frequently fatal clinical entity, characterized by noninfectious acute lung inflammation following allogeneic stem cell transplantation (SCT), the mechanisms of which are unclear. In this study, we demonstrate that immune suppression with cyclosporin after SCT limits T-helper cell (Th) 1 differentiation and interferon-γ secretion by donor T cells, which is critical for inhibiting interleukin (IL)-6 generation from lung parenchyma during an alloimmune response. Thereafter, local IL-6 secretion induces donor alloantigen-specific Th17 cells to preferentially expand within the lung, and blockade of IL-17A or transplantation of grafts lacking the IL-17 receptor prevents disease. Studies using IL-6(-/-) recipients or IL-6 blockade demonstrate that IL-6 is the critical driver of donor Th17 differentiation within the lung. Importantly, IL-6 is also dysregulated in patients undergoing clinical SCT and is present at very high levels in the plasma of patients with IPS compared with SCT recipients without complications. Furthermore, at the time of diagnosis, plasma IL-6 levels were higher in a subset of IPS patients who were nonresponsive to steroids and anti-tumor necrosis factor therapy. In sum, pulmonary-derived IL-6 promotes IPS via the induction of Th17 differentiation, and strategies that target these cytokines represent logical therapeutic approaches for IPS.
authors: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors: Antiopi
authors: A
authors: Varelias
authors: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors: Kate H
authors: KH
authors: Gartlan
authors: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors: Ellen
authors: E
authors: Kreijveld
authors: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors: Stuart D
authors: SD
authors: Olver
authors: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors: Mary
authors: M
authors: Lor
authors: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors: Rachel D
authors: RD
authors: Kuns
authors: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors: Katie E
authors: KE
authors: Lineburg
authors: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors: Bianca E
authors: BE
authors: Teal
authors: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors: Neil C
authors: NC
authors: Raffelt
authors: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors: Melody
authors: M
authors: Cheong
authors: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors: Kylie A
authors: KA
authors: Alexander
authors: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors: Motoko
authors: M
authors: Koyama
authors: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors: Kate A
authors: KA
authors: Markey
authors: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; Department of Bone Marrow Transplantation, The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia;
authors: Elise
authors: E
authors: Sturgeon
authors: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; Department of Bone Marrow Transplantation, The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia;
authors: Justine
authors: J
authors: Leach
authors: Division of Hematology and Oncology, Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI;
authors: Pavan
authors: P
authors: Reddy
authors: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; Department of Bone Marrow Transplantation, The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia;
authors: Glen A
authors: GA
authors: Kennedy
authors: Division of Hematology and Oncology, Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI;
authors: Gregory A
authors: GA
authors: Yanik
authors: Masonic Cancer Center and Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN;
authors: Bruce R
authors: BR
authors: Blazar
authors: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; Department of Bone Marrow Transplantation, The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia;
authors: Siok-Keen
authors: SK
authors: Tey
authors: Envoi Specialist Pathologists, Brisbane, QLD, Australia; and.
authors: Andrew D
authors: AD
authors: Clouston
authors: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors: Kelli P A
authors: KP
authors: MacDonald
authors: Department of Oncology, Blood and Marrow Stem Cell Transplantation Program, Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD.
authors: Kenneth R
authors: KR
authors: Cooke
authors: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; Department of Bone Marrow Transplantation, The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia;
authors: Geoffrey R
authors: GR
authors: Hill
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D000818:Animals; D016572:Cyclosporine / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology*; D015850:Interleukin-6 / Q000276:immunology*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D033581:Stem Cell Transplantation / Q000009:adverse effects*; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; D020381:Interleukin-17; D015850:Interleukin-6; D007371:Interferon-gamma; D016572:Cyclosporine