Original Article
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World J Gastroenterol. Feb 7, 2013; 19(5): 682-691
Published online Feb 7, 2013. doi: 10.3748/wjg.v19.i5.682
Interleukin-17 plays a critical role in the acute rejection of intestinal transplantation
Jian-Jun Yang, Fan Feng, Liu Hong, Li Sun, Meng-Bin Li, Ran Zhuang, Feng Pan, Ying-Mei Wang, Wei-Zhong Wang, Guo-Sheng Wu, Hong-Wei Zhang
Jian-Jun Yang, Fan Feng, Liu Hong, Li Sun, Meng-Bin Li, Wei-Zhong Wang, Guo-Sheng Wu, Hong-Wei Zhang, Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China
Ran Zhuang, Department of Immunology, Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China
Feng Pan, Department of Medical Statistics, Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China
Ying-Mei Wang, Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China
Author contributions: Yang JJ, Feng F, Hong L, and Sun L contributed equally to the work; Yang JJ and Feng F designed and performed all the animal experiments, and drafted the manuscript; Hong L assisted in in vivo animal experiments; Sun L assisted in biochemical experiments; Zhuang R assisted in immunological experiments; Wang YM assisted in hematoxylin eosin and immunofluorescence staining; Pan F assisted in experiment design, and carried out data collection and data analysis; Li MB, Wang WZ and Wu GS participated in human intestinal transplantation; Zhang HW, as director of the department, coordinated its execution and design, and revised the final version of the manuscript; all authors read and approved the present version of the manuscript.
Supported by Grants from Scientific Technology Research Development Project of Shaanxi in part, No. 2011K14-05-01, No. 2008K12-01; and a Grant from the National Natural Scientific Foundation of China, No. 31100643
Correspondence to: Hong-Wei Zhang, Professor, Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China. hongwzh@126.com
Telephone: +86-29-84771507 Fax: +86-29-82539041
Received: September 13, 2012
Revised: December 11, 2012
Accepted: December 15, 2012
Published online: February 7, 2013
Processing time: 145 Days and 19.2 Hours
Abstract

AIM: To investigate the role of interleukin (IL)-17 in small bowel allograft rejection.

METHODS: We detected the expression of helper T cell 17 (Th17) cells in biopsy specimens from 3 cases of living small bowel transplantation in our department through immunofluorescence stain. We then established a rat heterotopic small bowel transplantation model. The rats were sacrificed on the 1st, 2nd, 3rd, 5th, and 7th d after small bowel transplantation. The degrees of transplantation rejection in rat intestine graft were examined through hematoxylin eosin (HE) stain, and the expression of Th17 cells in rat intestine graft were detected through immunofluorescence stain. In addition, the recipient rats undergoing intestinal transplantation were administrated with mouse-anti-rat IL-17 monoclonal antibody (mAb), and the survival of rats was analyzed. The recipient rats which received mouse-anti-rat IL-17 mAb treatment were sacrificed on the 1st, 2nd, 3rd, 5th, and 7th d after small bowel transplantation. The degrees of transplantation rejection and the expression of Th17 cells in rat intestine graft were detected through HE and immunofluorescence stain. The expression of IL-17, IL-1β, tumor necroses factor receptor-α (TNF-α), IL-6, and IL-8 in the intestine graft or serum were also detected.

RESULTS: The expressions of Th17 cells ran parallel with the degree of acute rejection in human intestine grafts. The intestine graft rejection of rats was aggravated with prolonged duration after intestinal transplantation, and the expressions of Th17 cells were also correlated with the degree of acute rejection in rat intestine grafts. Administration of mouse-anti-rat IL-17 mAb prolonged the survival of rats after small bowel transplantation (P < 0.001). Furthermore, we found that the administration of mouse-anti-rat IL-17 mAb significantly decreased the intensity of CD4+IL-17+ Th17 cells in intestine grafts on the 2nd, 3rd, 5th, and the 7th d (97.22 ± 4.05 vs 12.45 ± 2.02 on the 7th d, P < 0.0001), and suppressed the severity of acute rejection. The expression of IL-17 in the intestine graft declined after mouse-anti-rat IL-17 mAb administration on the 2nd, 3rd, 5th, and the 7th d (0.88 ± 0.03 vs 0.35 ± 0.02 on the 7th d, P < 0.0001). We also detected the IL-17 serum level and found that the IL-17 level reduced from the 1st d to the 7th d (6.52 ± 0.18 ng/mL vs 2.04 ± 0.15 ng/mL on the 7th d, P < 0.0001). No significant difference in the level of IL-17 mRNA in the intestine graft was identified between the two groups. The levels of IL-1β, TNF-α, IL-6, and IL-8 mRNA in the intestine graft after the administration of mouse-anti-rat IL-17 mAb were also tested. We found that on the 3rd, 5th, and 7th d after intestinal transplantation, administration of mouse-anti-rat IL-17 mAb significantly inhibited the levels of IL-1β (12.11 ± 1.16 vs 1.27 ± 0.15 on the 7th d, P < 0.001), TNF-α (27.37 ± 2.60 vs 1.06 ± 0.26 on the 7th d, P < 0.001), IL-6 (21.43 ± 1.79 vs 1.90 ± 0.32 on the 7th d, P < 0.001), and IL-8 (20.44 ± 1.44 vs 1.34 ± 0.20 on the 7th d, P < 0.001) mRNA in the intestine graft.

CONCLUSION: IL-17 may act as a promising and potent target for inhibiting acute rejection after small bowel transplantation.

Keywords: Interleukin-17; Helper T cell 17; Small bowel transplantation; Acute rejection; Monoclonal antibody