Background: Long-term outcomes after lung transplantation are markedly worse than for other organs. The mechanisms that determine lung transplant rejection are not clear. The role of IL-17 in graft rejection has recently been established, while the precise role of IL-17 and IL-17 producing cells and how they contribute to lung graft rejection are being actively investigated. In this study, we examined the role of Th17 mediated inflammatory responses after trachea and lung transplantation.

Methods: Murine orthotopic trachea or lung transplants were performed in wild type and RORγt^-/- (C57BL/6 background) mice using BALB/c donors. For IL-17 neutralization, recipients received 200 μg of anti-IL-17 mAbs i.p. on days -1, 1, 3, 5 and 7. Syngeneic transplants were also performed in wild type C57BL/6 mice using C57BL/6 donors. Lung transplant graft function was monitored by CT scan. Histology was performed on transplanted organs to examine transplant rejection and inflammatory cell infiltration. Lymphocytes were isolated from recipient draining lymph nodes or transplanted organs, and real-time RT-PCR for IL-6, IL-17 and IFNγ was then performed. Flow cytometry and immunohistochemistry were also utilized to characterize phenotypes of graft-infiltrating cells.

Results: The levels of IL-6 and IL-17 in allografts increased significantly compared to isografts (P<0.05) 3 days after transplantation. At day 14, the airway pseudostratified epithelia of trachea isografts maintained normal, without any proliferation of fibroblast in submucosa tissue. On the contrary, the pseudostratified epithelia of allografts changed into flat epithelium with fibroblast proliferation. Anti-IL-17 treatment preserved pseudostratified epithelia, however proliferation of fibroblast was observed. RORγt deficiency completely restored normal airway morphology. Similar inflammatory responses were also observed in lung grafts.

Conclusion: Th17 mediates early post-transplant airway inflammation after lung transplantation, and devoid of Th17 development or Th17 cytokine production abolishes epithelial inflammation and improves graft function and survival. Our findings have important implications for understanding the role of Th17 in lung transplant immunity and further indicate the critical importance for inhibiting Th17 cytokine production early after transplantation.

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