Pediatric autoimmune hepatitis shows a disproportionate decline of regulatory T cells in the liver and of IL-2 in the blood of patients undergoing therapy

Abstract

Background & AimsThe autoimmune hepatitis (AIH) is a chronic hepatitis driven by the adaptive immunity that affects all age groups. A functional and numerical regulatory T cell (Treg) defect has been reported in pediatric AIH (pAIH), while an intrahepatic increase in adult AIH (aAIH) patients has been detected in current research findings.MethodsTherefore, we quantified the intrahepatic numbers of Treg, T and B cells, as well as serum cytokine levels before and during therapy in pAIH.ResultsWe found a disproportional intrahepatic enrichment of Tregs in untreated pAIH compared to pediatric non-alcoholic fatty liver disease. The increase of Treg/total T cells was even more pronounced than in aAIH due to fewer infiltrating T and B cells. Portal densities of Treg, as well as total T and B cells, declined significantly during therapy. However, portal Treg densities decreased disproportionately, leading to even decreasing ratios of Treg to T and B cells during therapy. Out of 28 serum cytokines IL-2 showed the strongest (10fold) decrease under therapy. This decline of IL-2 was associated with decreasing intrahepatic Treg numbers under therapy. None of the baseline T and B cell infiltration parameters were associated with the subsequent treatment response in pAIH.ConclusionsIntrahepatic Tregs are rather enriched in untreated pAIH. The disproportional decrease of Tregs during therapy may be caused by a decrease of IL-2 levels. New therapies should, therefore, aim in strengthening intrahepatic immune regulation.

IL‐2/IL‐6 ratio correlates with liver function and recovery in acute liver injury patients

“…Here, we found that IL‐2 levels increased significantly with the improvement of liver injury, but IL‐6 decreased with treatment. For IL‐2, this result is consistent with those of many previous studies , although for IL‐6, this is somewhat surprising. It is possible that this observation may be due to the different detection time points studied.…”

Baseline IL-2 and the AIH score can predict the response to standard therapy in paediatric autoimmune hepatitis

“…Nonetheless, we did not detect significantly higher intrahepatic Treg numbers in patients with subsequent BR in the histological analysis of the present cohort. However, a disproportionate intrahepatic decline in Tregs under therapy was accompanied by a significant decline in IL-2 in the blood 32 . Although blood cytokine levels are not routine clinical parameters, the present results suggested that the predictive capacity of clinical parameters could be improved by non-routine parameters.…”

“…The predictive role of serum IgG levels in adult and paediatric AIH 13 , 32 point to a relevant role of the humoral immune response. AIH is considered to be mainly T cell especially Th1 driven 38 and in our study classical B cell cytokines in the peripheral blood were not predictive for the treatment response.…”

Budesonide in Autoimmune Hepatitis: The Right Drug at the Right Time for the Right Patient

“…In addition, steroid-and azathioprine-based therapies are leading to a preferential depletion of regulatory T cells over effector T cells, thereby potentially disturbing the long-term intrahepatic immune tolerance. 16,17 This local reduction of regulatory T cells seems to be associated with a worse treatment response potentially mediated by the lack of their survival factor interleukin-2. [16][17][18] This might be one reason for relapses frequently observed after discontinuation of immunosuppressive therapy.…”

“…16,17 This local reduction of regulatory T cells seems to be associated with a worse treatment response potentially mediated by the lack of their survival factor interleukin-2. [16][17][18] This might be one reason for relapses frequently observed after discontinuation of immunosuppressive therapy. With these recent pathophysiological insights into the intrahepatic immune milieu under therapy and in patients with incomplete treatment response, pharmacologically different and innovative approaches should be considered.…”