title: Interleukin-17 accelerates allograft rejection by suppressing regulatory T cell expansion.
abstract: BACKGROUND
  Interleukin-17 (IL-17), which is predominantly produced by T helper 17 cells distinct from T helper 1 or T helper 2 cells, participates 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.
  
  
  RESULTS
  Donor hearts from FVB mice were heterotopically transplanted into either C57BL/6J-IL-17-deficient (IL-17(-/-)) or -wild-type mice. Allograft survival was significantly prolonged in IL-17(-/-) recipient mice due to reduced local inflammation accompanied by decreased inflammatory cell recruitment and cytokine/chemokine expression. IL-17(-/-) recipient mice exhibited decreased IL-6 production and reciprocally enhanced regulatory T cell expansion, suggesting a contribution of regulatory T cells to prolonged allograft survival. Indeed, allografts transplanted into anti-CD25 mAb-treated IL-17(-/-) recipient mice (regulatory T cell-depleted) developed acute rejection similar to wild-type recipient mice. Surprisingly, we found that gamma delta T cells rather than CD4(+) and CD8(+) T cells were key IL-17 producers in the allografts. In support, equivalent allograft rejection was observed in Rag-2(-/-) recipient mice engrafted with either wild-type or IL-17(-/-) CD4(+) and CD8(+) T cells. Finally, hearts transplanted into gamma delta T cell-deficient mice resulted in decreased allograft rejection compared with wild-type controls.
  
  
  CONCLUSIONS
  During heart transplantation, (1) IL-17 is crucial for acceleration of acute rejection; (2) IL-17-deficiency enhances regulatory T cell expansion; and (3) gamma delta T cells rather than CD4(+) and CD8(+) T cells are a potential source of IL-17. IL-17 neutralization may provide a potential target for novel therapeutic treatment for cardiac allograft rejection.
authors.affiliation: Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Itoh
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kimura
authors.forename: Robert C
authors.initials: RC
authors.lastname: Axtell
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Velotta
authors.forename: Yongquan
authors.initials: Y
authors.lastname: Gong
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.forename: Naoki
authors.initials: N
authors.lastname: Kajiwara
authors.forename: Aya
authors.initials: A
authors.lastname: Nambu
authors.forename: Eri
authors.initials: E
authors.lastname: Shimura
authors.forename: Hideo
authors.initials: H
authors.lastname: Adachi
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Saito
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.forename: Katsuko
authors.initials: K
authors.lastname: Sudo
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
authors.forename: Robert C
authors.initials: RC
authors.lastname: Robbins
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakae
authors.forename: Michael P
authors.initials: MP
authors.lastname: Fischbein
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D006084:Graft Rejection / Q000473:pathology / Q000503:physiopathology*; D016027:Heart Transplantation / Q000473:pathology / Q000502:physiology*; D020381:Interleukin-17 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism / Q000473:pathology*; D058504:Th17 Cells / Q000378:metabolism / Q000473:pathology; D014184:Transplantation, Homologous
chemical_list: D020381:Interleukin-17; D016692:Receptors, Antigen, T-Cell, gamma-delta