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Blood, 1 September 2008, Vol. 112, No. 5, pp. 2101-2110.
Prepublished online as a Blood First Edition Paper on July 2, 2008; DOI 10.1182/blood-2007-12-126987.
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TRANSPLANTATION
Absence of donor Th17 leads to augmented Th1 differentiation and exacerbated acute graft-versus-host disease
Tangsheng Yi13,
Dongchang Zhao2,3,
Chia-Lei Lin2,3,
Chunyan Zhang2,3,
Ying Chen2,3,
Ivan Todorov2,
Thomas LeBon1,
Fouad Kandeel2,
Stephen Forman3, and
Defu Zeng13
1 Graduate School of Biological Science,
2 Department of Diabetes, Endocrinology & Metabolism, and
3 Division of Hematology & Hematopoietic Cell Transplantation, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA
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 arthritis, 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) donor 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 inflammatory chemokines. Administration of recombinant IL-17 and neutralizing IFN- in the recipients given IL-17–/– donor cells ameliorated the acute GVHD. Furthermore, the regulation of Th1 differentiation by IL-17 or Th17 may be through its influence on host DCs. Our results indicate that donor Th17 cells can down-regulate Th1 differentiation and ameliorate acute GVHD in allogeneic recipients, and that treatments neutralizing proinflammatory cytokine IL-17 may augment acute GVHD as well as other inflammatory autoimmune diseases.
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