TRANSPLANTATION Absence of donor Th17 leads to augmented Th1 differentiation and exacerbated acute graft-versus-host disease

Th17 is a newly identified T-cell lineage that secretes proinflammatory cytokine IL-17. Th17 cells have been shown to play a critical role in mediating autoimmune diseases such as EAE, colitis, and arthri-tis, but their role in the pathogenesis of graft-versus-host disease (GVHD) is still unknown. Here we showed that, in an acute GVHD model of C57BL/6 (H-2b) do-nor to BALB/c (H-2d) recipient, IL-17/ donor T cells manifested an augmented Th1 differentiation and IFN- production and induced exacerbated acute GVHD. Severe tissue damage mediated by IL-17/ donor T cells was associated with increased Th1 infiltration, up-regulation of chemokine receptors by donor T cells, and enhanced tissue expression of inflam-matory chemokines. Administration of re-combinant IL-17 and neutralizing IFN- in the recipients given IL-17/ donor cells ameliorated the acute GVHD. Further-more, the regulation of Th1 differentiation by IL-17 or Th17 may be through its influence on host DCs. Our results indi-cate that donor Th17 cells can down-regulate Th1 differentiation and amelio-rate acute GVHD in allogeneic recipients, and that treatments neutralizing proin-flammatory cytokine IL-17 may augment acute GVHD as well as other inflamma-tory autoimmune diseases. (Blood. 2008; 112:2101-2110