Abstract 20478: Interleukin-17 Accelerates Allograft Rejection by Suppressing Regulatory T Cell Expansion
Background: Interleukin-17 (IL-17), which is dominantly produced by Th17 cells distinct from Th1 or Th2 cells, is considered to be involved in the pathogenesis of infectious, autoimmune and allergic disorders. However, the precise role in allograft rejection remains uncertain. In the present study, we investigated the role of IL-17 in acute allograft rejection using IL-17-deficient mice.
Methods and Results: In acute rejection (fully MHC-mismatch), donor hearts of FVB mice were heterotopically transplanted into either (a) C57BL/6-IL17-deficient (IL-17−/− ) or (b) C57BL/6-wild-type (WT) mice (n=6 each). Overall graft survival was initially determined. IL-17−/− recipient mice exhibited decreased IL-6 production and reciprocally enhanced regulatory T cell (Treg) expansion, resulting in reduced local inflammation, cytokine expression profiles, and prolongation of allograft survival (IL-17−/− vs WT, 35±35 vs. 9.6±0.6 days, n=20, P<0.05). On the other hand, transplanted allografts were comparably rejected between WT recipient mice and IL-17−/− recipient mice which were Treg depleted by administration of anti-CD25 mAb. Surprisingly, the major producer of IL-17 was γδ T cells rather than CD4+ and CD8+ T cells in the allografts transplanted into WT recipients. Supportively, the allografts transplanted into Rag-2−/− mice which had been engrafted with IL-17−/− CD3+ T cells was similarly rejected to those with WT CD3+ T cells. However, the survival of allografts transplanted into γδ TCR-deficient mice was significantly prolonged compared with that into WT recipient mice (γδ TCR-deficient vs WT, 14.4±8.3 vs. 8.6±1.2 days, n=18, P<0.01). These observations suggest that IL-17, particularly γδ T cell, but neither CD4+ nor CD8+ T cell, -derived IL-17, is crucial for the pathogenesis of acute rejection.
Conclusions: (1) IL-17 is crucial for the acceleration of acute rejection during heart transplantation; (2) γδ T cells are potential producers of IL-17 during acute rejection and important for allograft survival; (3) IL-17 blockade may prolong allograft survival via enhanced regulatory T cell expansion. IL-17-neutralization may provide a potential target for novel therapeutic treatment for cardiac allograft rejection.
- © 2010 by American Heart Association, Inc.