Lung parenchyma–derived IL-6 promotes IL-17A–dependent acute lung injury after allogeneic stem cell transplantation. — ASN Events
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  2. Poster Session 2
  3. Lung parenchyma–derived IL-6 promotes IL-17A–dependent acute lung injury after allogeneic stem cell transplantation.

Lung parenchyma–derived IL-6 promotes IL-17A–dependent acute lung injury after allogeneic stem cell transplantation. (#188)

Antiopi Varelias 1 , Kate H Gartlan 1 , Ellen Kreijveld 1 , Stuart D Olver 1 , Mary Lor 1 , Rachel D Kuns 1 , Katie E Lineburg 1 , Bianca E Teal 1 , Neil C Raffelt 1 , Melody Cheong 1 , Kylie A Alexander 1 , Motoko Koyama 1 , Kate A Markey 1 , Elise Sturgeon 1 2 , Justine Leach 1 2 , Pavan Reddy 3 , Glen Kennedy 1 2 , Gregory Yanik 3 , Bruce R Blazar 4 , Siok K Tey 1 2 , Andrew Clouston 5 , Kelli PA MacDonald 1 , Kenneth R Cooke 6 , Geoffrey R Hill 1 2
  1. QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
  2. Bone Marrow Transplantation, The Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia
  3. Division of Hematology and Oncology, Blood and Marrow Transplantation Program, The University of Michigan, Ann Arbor, Michigan, USA
  4. Masonic Cancer Center and Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA
  5. Envoi Specialist Pathologists, Brisbane, QLD, AUSTRALIA
  6. Deparment of Oncology, Blood and Marrow Stem Cell Transplantation Program, Sidney Kimmel Cancer Center & Johns Hopkins University School of Medicine, Baltimore, MD, USA

Idiopathic Pneumonia Syndrome (IPS) is a relatively common, frequently fatal clinical entity characterized by non-infectious acute lung inflammation following allogeneic stem cell transplantation (SCT), the mechanisms of which are unclear. Here we demonstrate that immune suppression with cyclosporin after SCT limits Th1 differentiation and IFN-gamma secretion by donor T cells which is critical for inhibiting 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. Interestingly, IL-17A is also secreted by recipient gamma-delta T cells early after SCT. 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 was present at very high levels in the plasma of patients with IPS compared to SCT recipients without complications. Furthermore, at the time of diagnosis, plasma IL-6 levels were higher in a subset of IPS patients who were non-responsive to steroids and anti-TNF 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.