Th17 and Th1 play distinct roles in obliterative bronchiolitis pathogenesis after transplantation.

Abstract

Abstract Development of obliterative bronchiolitis (OB) is the biggest obstacle that limits long-term allograft survival and clinical application of lung transplantation. Mouse orthotopic trachea or lung transplantations were utilized to examine roles of Th17 and Th1 during OB pathogenesis after transplantation. Allografts of wild type recipients displayed elevated levels of Th1 and Th17 cytokines IFNγ, IL-6 and IL-17 expression. Recipients deficient in Th1 key transcriptional factor T-bet resulted in decreased cell infiltration and improved airway integrity in orthotopic transplanted trachea grafts; Lack of Th2 transcriptional factor Stat6 had little effect; While absence of Th17 master transcriptional factor RORγt had striking effects in abolishing airway epithelial injury, a leading factor of OB pathogenesis. Administering anti-IL-6 or anti-IL-17 but not anti-IFNγ mAbs restored normal airway epithelial morphology. Furthermore, we found that anti-CD40L treatment resulted in increased FoxP3 and regulatory T cells, and decreased IFNγ expression; However it had very limited effect on IL-17 suppression and airway epithelial protection. While CTLA4-Ig treatment significantly inhibit IL-17 expression and reduced epithelial injury, and the combination of CTLA4-Ig and anti-CD40L markedly restored airway morphology of grafts. Together, our findings provide new insights for understanding Th17 and Th1 responses during OB pathogenesis and demonstrate the critical importance of suppressing Th17 for OB development after transplantation.