Background: The mechanisms leading to de novo autoimmune hepatitis (d-AIH) remain unclear. Regulatory T cells (T-regs) can be induced to differentiate into inflammation associated Th17 cells in-vitro. Adoptive transfer of differentiated T-regs has been shown to lead to autoimmunity. We hypothesize that T-regs from patients with d-AIH are dysfunctional, differentiate into Th17 cells & that detection of differentiated T-regs directly at the site of inflammation would support their role in the perpetuation of chronic autoimmunity in d-AIH. Methods: A functional assessment of T-regs was performed in vitro using flow cytometry & their potential to produce IL-17 was studied using electrochemiluminescence. Detection of FoxP3⁺IL-17A producing cells within inflammatory infiltrates of d-AIH & normal liver transplant (LT) recipient liver biopsies was performed using immunohistochemistry. PBMC’s from LT recipients (n=21) & archived liver tissue was used for this assessment. Results: T-regs from recipients with d-AIH (n=14) suppressed T-cell proliferation at significantly lower levels than the T-regs from recipients without d-AIH (n=7) (p=0.003). T-regs from both groups of recipients suppressed IFNΓ secretion within culture supernatants, (LT controls T-regs better than d-AIH T-regs p=0.02), however d-AIH T-regs suppressed IL-17 secretion at significantly lower levels than the T-regs obtained from LT controls (p=0.026). Ex-vivo stimulation of T-regs from recipients with d-AIH resulted in the production IL-17. CD4⁺ cells expressing both FoxP3 and IL-17A were present in inflammatory infiltrates of liver biopsies with d-AIH but absent in liver biopsies of LT recipients without d-AIH. The mean duration from time of transplant & calcineurin inhibitor (CNI) level at time of blood draw were not significantly different between the 2 groups (p=0.32 & p=0.6 respectively), suggesting that impaired T-reg function in recipients with d-AIH was not a result of over suppression with CNI’s. Conclusion: The presence of FoxP3⁺ IL-17A-producing cells within the inflammatory infiltrate of liver biopsies with d-AIH; the reduced ability of d-AIH T-regs to suppress IL-17 secretion; & the increased IL-17 production seen in d-AIH T-regs; suggests that the conversion of T-regs into IL-17 producing cells might take place in vivo in humans. This in turn might inadvertently contribute to the perpetuation of chronic autoimmunity in d-AIH.

« Back to 2013 American Transplant Congress