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Interleukin-17 accelerates allograft rejection by suppressing regulatory T cell expansion.
MedLine Citation:
PMID:  21911812     Owner:  NLM     Status:  In-Data-Review    
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. Methods and 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.
Satoshi Itoh; Naoyuki Kimura; Robert C Axtell; Jeffrey B Velotta; Yongquan Gong; Xi Wang; Naoki Kajiwara; Aya Nambu; Eri Shimura; Hideo Adachi; Yoichiro Iwakura; Hirohisa Saito; Ko Okumura; Katsuko Sudo; Lawrence Steinman; Robert C Robbins; Susumu Nakae; Michael P Fischbein
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Circulation     Volume:  124     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-09-13     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  S187-96     Citation Subset:  AIM; IM    
Department of Cardiothoracic Surgery, Stanford University School of Medicine, 300 Pasteur Drive, CVRB MC 5407, Stanford, CA 94305.
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