The majority of transplanted intestines still falls victim to allograft enteropathy, the underlying mechanisms of which are poorly understood. The purpose of this study was to test the hypothesis that Th17-mediated alloimmune responses play a major role in the pathogenesis of intestinal transplant (ITx) rejection in humans.

To precisely explore the role of Th17-mediated alloimmunity in human ITx, we analyzed intestinal allograft biopsy samples from 10 ITx recipients with acute cellular rejection. Normal baseline biopsy samples taken from before the onset of rejection were used as controls. Samples were confirmed for rejection by histology, and were further characterized in terms of the phenotype, transcription factor and effector cytokine profile of graft-infiltrating cells by RT-PCR arrays and flow cytometry.

First, we explored the phenotype of graft-infiltrating cells in rejecting intestinal transplants and found significantly elevated expression levels of activation and costimulatory markers such as CCR6, CD28, ICOS, and CD25 in the rejection vs control samples (31.2, 4.2, 3.9, 2.1 fold, respectively; p<0.05), suggesting that activated graft-infiltrating CCR6⁺ T cells with Th17 commitment may be key effector cells in intestinal allograft rejection. To verify this, we next determined the transcription factor and cytokine profile of rejection vs baseline control samples and discovered strikingly elevated expression levels of the Th17 hallmark transcription factors RORα, Runx1, and IRF4 (45.5, 13.9, 3.7 fold, respectively; p<0.05) as well as significantly higher levels of the Th17 effector cytokines IL-21 and IL-17C in the rejection samples (10.1, 4.5 fold, respectively; p<0.05), confirming that Th17 cells may be critically involved in intestinal allograft rejection. Thus, we next studied potential underlying mechanisms upstream of Th17 induction and found much higher expression levels of IL-6 and TGF-β as well as of IL-23 and IL-1-receptor-1 in rejection samples (10.5, 3.0 & 6.3, 3.8 fold, respectively; p<0.05), indicating that the proinflammatory milieu in intestinal transplantation induces Th17-mediated alloimmune responses via both IL-6/TGF-β and IL-23/IL-1β pathways.

In conclusion, our study indicates that Th17-mediated alloimmune responses may play a significant, and previously unknown, role in intestinal allograft rejection in humans, which may be of high clinical relevance.

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