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Interleukin-17 Accelerates Allograft Rejection by Suppressing Regulatory T Cell Expansion

Authors :
Satoshi Itoh
Naoyuki Kimura
Eri Shimura
Robert C. Axtell
Yoichiro Iwakura
Naoki Kajiwara
Ko Okumura
Michael P. Fischbein
Susumu Nakae
Hirohisa Saito
Lawrence Steinman
Hideo Adachi
Katsuko Sudo
Robert C. Robbins
Aya Nambu
Xi Wang
Yongquan Gong
Jeffrey B. Velotta
Source :
Circulation. 124
Publication Year :
2011
Publisher :
Ovid Technologies (Wolters Kluwer Health), 2011.

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. 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.

Details

ISSN :
15244539 and 00097322
Volume :
124
Database :
OpenAIRE
Journal :
Circulation
Accession number :
edsair.doi.dedup.....3498b3a68105874652252be37ea6b961
Full Text :
https://doi.org/10.1161/circulationaha.110.014852