Background: Obliterative bronchiolitis is the major obstacle limiting long-term allograft survival of lung transplantation. Airway epithelium is the primary target in obliterative airway diseases. Th17 cytokines and signals play critical roles in mediating inflammatory responses and are involved in transplant graft rejection. In this study, we performed murine orthotopic trachea transplantations and examined the roles of Th17 development signals and IL-17 in airway epithelial injury after transplantation.

Methods: Murine orthotopic allogeneic trachea transplants were implemented in wild type and RORγt^-/- (C57BL/6 background) mice utilizing BALB/c donors. Recipients received anti-IL-6 mAbs or C188-9, an inhibitor of STAT3 activation, to suppress Th17 development signals, and anti-IL-17 mAbs for IL-17 neutralization. Syngeneic transplants were also performed in wild type C57BL/6 mice using C57BL/6 donors. Airway epithelial injury and inflammatory cell infiltration of transplanted tracheas were verified by histopathologic analysis; IL-6, IL-17 and IFNγ expressions in trachea grafts were examined by real-time RT-PCR.

Results: The expression levels of IL-17 and IL-6 in allografts were markedly elevated compared to those in isografts 3 days after transplantation. At day 14, the airway structure of isografts maintained normal, whereas the pseudostratified ciliated columnar epithelia of allografts changed into flat epithelia with fibroblast proliferation and inflammatory cell infiltration in submucosal tissue. Administration of anti-IL-6 or STAT3-inhibitor improved airway epithelial integrity of allografts; however fibroblast proliferation along with cell infiltration remained observed. Anti-IL-17 treatment or RORγt deficiency completely restored normal epithelial morphology in trachea allografts.

Conclusion: Our results demonstrate that IL-17 is crucial to post-transplant airway inflammation and epithelial damage, and further indicate that, in addition to blockade of IL-6/STAT3 Th17 development pathways, suppression of IL-17 from other sources is necessary for airway epithelial protection and allograft survival after transplantation.

CITATION INFORMATION: Zhang R., Fang H., Chen Q., Ochando J., Ding Y., Xu J. IL-17 is Critical for Airway Epithelial Injury after Transplantation Am J Transplant. 2017;17 (suppl 3).

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