Background: Development of obliterative bronchiolitis (OB) is the biggest obstacle that limits long-term allograft survival and clinical application of lung transplantation, and the precise mechanisms of OB pathogenesis remain unclear. Injury of airway epithelial cells is a leading factor of OB pathogenesis, as the degree of epithelial injury is closely correlated with the development of OB after lung transplantation. In this study, we utilized murine orthotopic trachea transplantation to examine the roles of Th17 during OB pathogenesis.

Methods: Murine orthotopic trachea transplants were performed in wild type, T-bet^-/- and RORγt^-/- (C57BL/6 background) mice using BALB/c donors. For cytokine neutralization, recipients received 200 [mu]g of anti-IL-17, anti-IFNγ or anti-IL-6 mAbs i.p. on days -1, 1, 3, 5 and 7. For immune suppression, recipients received anti-CD40L mAbs (500 [mu]g), CTLA4-Ig fusion protein (100 [mu]g) or their combination i.p. on days 0 and 1. Syngeneic transplants were also performed in wild type C57BL/6 mice using C57BL/6 donors. Histology was performed on transplanted organs to examine transplant rejection and inflammatory cell infiltration. Graft infiltrating cells were isolated and real-time RT-PCR was performed for IL-6, IL-17, IFNγ and FoxP3 expression.

Results: The levels of IFNγ and IL-17 in allografts increased significantly compared to isografts (P<0.05) 3 days after transplantation. At day 15, the airway pseudostratified epithelia of trachea isografts maintained normal, while the pseudostratified epithelia of allografts changed into flat epithelia with fibroblast proliferation in submucosal tissue. Anti-IL-6 or anti-IL-17, but not anti-IFNγ treatment preserved pseudostratified epithelia. RORγt but not T-bet deficiency restored normal airway epithelial morphology. Furthermore, CTLA4-Ig is more effective for IL-17 suppression and airway epithelial protection than anti-CD40L.

Conclusion: Devoid of Th17 development or Th17 cytokine production abolishes airway epithelial injury and improves graft function and survival. Our findings revealed a critical and distinct role of Th17 in airway injury, inflammation and lung transplant immunity, further indicating the importance of inhibiting Th17 cytokine production early after transplantation.

CITATION INFORMATION: Xu J, Zhang Y, Wang L, Li X, Chen R, Zhang R, Ding Y. Th17 Development Is Critical for Airway Epithelial Injury After Transplantation. Am J Transplant. 2016;16 (suppl 3).

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