A. Allograft rejection remains a significant source of mortality and morbidity in intestinal transplant (ITx) recipients. However, the underlying mechanisms remain unclear. 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.

B. We obtained ITx allograft biopsies from recipients with acute cellular rejection (ACR), as well as a control ITx cohort with normal biopsies. Phenotypic analysis of cells was conducted by polychromatic flow cytometry and IHC. Graft-infiltrating cells were flow-sorted and real-time PCR (rtPCR) was performed to investigate effector cytokine and transcriptional factor profiles.

C. Our previous studies suggested that ITx allograft rejection may be critically mediated by CCR6 expressing Th17 cells as indicated by markedly elevated expression of Th17 related transcription profile in ACR versus pre-rejection control biopsy samples. Based on this we tested the hypothesis that CCR6+ Th17 are truly mediating ITx allograft rejection by analyzing CD4+/CCR6+ T-cells in ACR versus healthy control recipients via flow cytometry. Importantly, we found a significant increase in CCR6+ Th17 cells in rejection versus control bxs (55.6% v 26%, p<0.05). This Th17 phenotype was specific for allograft rejection since recipients with active allograft infections did not show such an increase in Th17 cells. Further subset analyses of flow-sorted CD4+/CCR6+ cells confirmed high expression levels of the hallmark transcription factor RORα and the signature effector cytokine IL-17, corroborating that IL-17 producing CCR6+ cells drive ITx rejection. Finally, we tested the hypothesis that proinflammatory dendritic cells induce Th17 responses in ITx by studying flow-sorted intestinal CX3CR1+ myeloid dendritic cells, which are implicated in regulating proinflammatory T-cell alloimmune responses. We found a pro-inflammatory Th17-related mRNA profile in the flow sorted dendritic cells as indicated by high expression of IL-1β, IL6, IL-23, and TNFα, suggesting that proinflammatory CX3CR1+ dendritic cells induce Th17-mediated responses to allograft rejection.

D: In conclusion, this study shows that Th17-mediated alloimmune responses play a significant role in intestinal allograft rejection in humans, which is of high clinical significance.

CITATION INFORMATION: Kaiser J, Cosentino C, Shukla A, Desai C, Girlanda R, Hawksworth J, Matsumoto C, Zasloff M, Fishbein T, Kroemer A. IL-17-Producing CCR6⁺CD4⁺ Th17 Cells Drive Intestinal Allograft Rejection in Humans. Am J Transplant. 2016;16 (suppl 3).

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