Role of interleukin-17A in early graft rejection after orthotopic lung transplantation in mice.
BACKGROUND
The cellular and molecular mechanisms underlying lung allograft rejection remain poorly understood. We investigated the potential role of interleukin (IL)-17A in lung transplant rejection in a mouse model, because previous studies in clinical and rodent models have implicated IL-17A in both acute and chronic rejection.


METHODS
To generate an orthotopic lung transplantation model, lungs from C57BL/6 or BALB/c mice were transplanted into C57BL/6 mice (isograft and allograft models, respectively). The effects of anti-IL-17A treatment in allograft recipients were investigated. The histological features and rejection status of isografts and allografts were assessed at 3, 7, and 28 days after transplantation, and differences in graft infiltrating cells and mRNA expression of relevant cytokines were quantified at 3 and 7 days after transplantation.


RESULTS
As expected, isografts showed no obvious signs of rejection, whereas allografts exhibited minimal-to-mild rejection (grade A1-A2) by day 3 and moderate-to-severe rejection (grade A3-A4) by day 7, without evidence of obliterative bronchiolitis (OB). However, by 28 days, evidence of OB was observed in 67% (2/3) of allografts and severe rejection (grade A4) was observed in all. IL-17 mRNA expression in allografts was increased with rejection, and interferon (IFN)-γ and IL-6 mRNA expression levels followed a similar pattern. In contrast, IL-22 expression in allografts was only slightly increased. Antibody (Ab) neutralization of IL-17A diminished the signs of acute rejection at 7 days after transplantation in allografts, and this early protection was accompanied by a decrease in cellular stress according to histological evaluation, suggesting the involvement of IL-17A in the development of early post-transplantation lesions.


CONCLUSIONS
Our data indicate that IL-17A is important in the pathophysiology of allograft rejection, and neutralization of IL-17A is a potential therapeutic strategy to preventing lung transplant rejection.
1 Department of Thoracic Surgery, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China ; 2 Department of Immunology, Capital Medical University, Beijing 100069, China.
Qi-Rui
QR
Chen
1 Department of Thoracic Surgery, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China ; 2 Department of Immunology, Capital Medical University, Beijing 100069, China.
Li-Feng
LF
Wang
1 Department of Thoracic Surgery, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China ; 2 Department of Immunology, Capital Medical University, Beijing 100069, China.
Si-Si
SS
Xia
1 Department of Thoracic Surgery, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China ; 2 Department of Immunology, Capital Medical University, Beijing 100069, China.
Ya-Mei
YM
Zhang
1 Department of Thoracic Surgery, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China ; 2 Department of Immunology, Capital Medical University, Beijing 100069, China.
Jiang-Nan
JN
Xu
1 Department of Thoracic Surgery, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China ; 2 Department of Immunology, Capital Medical University, Beijing 100069, China.
Hui
H
Li
1 Department of Thoracic Surgery, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China ; 2 Department of Immunology, Capital Medical University, Beijing 100069, China.
Yao-Zhong
YZ
Ding
Lung transplantation; interleukin-17A; mouse model; rejection