Interleukin-17 plays a critical role in the acute rejection of intestinal transplantation

Abstract

To investigate the role of interleukin (IL)-17 in small bowel allograft rejection. 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 1(st), 2(nd), 3(rd), 5(th), and 7(th) 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 1(st), 2(nd), 3(rd), 5(th), and 7(th) 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. 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 2(nd), 3(rd), 5(th), and the 7(th) d (97.22 ± 4.05 vs 12.45 ± 2.02 on the 7(th) 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 2(nd), 3(rd), 5(th), and the 7(th) d (0.88 ± 0.03 vs 0.35 ± 0.02 on the 7(th) d, P < 0.0001). We also detected the IL-17 serum level and found that the IL-17 level reduced from the 1(st) d to the 7(th) d (6.52 ± 0.18 ng/mL vs 2.04 ± 0.15 ng/mL on the 7(th) 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 3(rd), 5(th), and 7(th) 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 7(th) d, P < 0.001), TNF-α (27.37 ± 2.60 vs 1.06 ± 0.26 on the 7(th) d, P < 0.001), IL-6 (21.43 ± 1.79 vs 1.90 ± 0.32 on the 7(th) d, P < 0.001), and IL-8 (20.44 ± 1.44 vs 1.34 ± 0.20 on the 7(th) d, P < 0.001) mRNA in the intestine graft. IL-17 may act as a promising and potent target for inhibiting acute rejection after small bowel transplantation.