Zhang Chunpan, Sun Guangyong, Jin Hua, Wei Yunxiong, Zheng Shimeng, Wang Xiyu, Zhao Xinyan, Zhang Dong, Jia Jidong
Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
BMC Med. 2025 Apr 7;23(1):209. doi: 10.1186/s12916-025-04043-9.
Primary biliary cholangitis (PBC) is a liver-specific autoimmune disease. Treatment of PBC with ursodeoxycholic acid (UDCA) is not sufficient to prevent disease progression. Our previous study revealed that the number of hepatic double-negative T cells (DNT), which are unique regulatory T cells, was reduced in PBC patients. However, whether replenishment of DNT can prevent the progression of PBC remains unclear.
DnTGFβRII (Tg) mice and 2OA-BSA-immunized mice received DNT alone or in combination with oral UDCA. After 6-12 weeks of treatment, these mice were assessed for serological changes, liver pathological manifestations and intrahepatic immune responses.
Adoptive transfer of DNT alone significantly decreased serum levels of alanine transaminase (ALT), aspartate transaminase (AST), antimitochondrial antibody M2 (AMA-M2) and immunoglobulin M (IgM) in both Tg and 2OA-BSA-immunized PBC mouse models. In addition, DNT exhibited a strong killing effect on liver T cells and strong inhibition of their proliferation, but did not significantly improve the histology of PBC liver. However, combination therapy with DNT and oral UDCA predominantly ameliorated liver inflammation and significantly inhibited hepatic T and B cells. In vitro further study revealed that UDCA up-regulated the proliferation of DNT, increased the expression of the functional molecule perforin, and reduced the expression of NKG2A and endothelial cell protein C receptor (EPCR) through the farnesoid X receptor (FXR)/JNK signaling pathway in both mice and human DNT.
A single transfer of DNT ameliorated PBC in mice, while combination therapy of DNT with oral UDCA displayed a better efficacy, with stronger inhibition of hepatic T and B cells. This study highlights the potential application of DNT-based combination therapy for PBC, especially for UDCA non-responders.
原发性胆汁性胆管炎（PBC）是一种肝脏特异性自身免疫性疾病。用熊去氧胆酸（UDCA）治疗PBC不足以预防疾病进展。我们之前的研究表明，作为独特调节性T细胞的肝脏双阴性T细胞（DNT）数量在PBC患者中减少。然而，补充DNT是否能预防PBC进展仍不清楚。
DnTGFβRII（Tg）小鼠和经2OA-BSA免疫的小鼠单独或联合口服UDCA接受DNT。治疗6-12周后，评估这些小鼠的血清学变化、肝脏病理表现和肝内免疫反应。
单独过继转移DNT可显著降低Tg和经2OA-BSA免疫的PBC小鼠模型中血清丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）、抗线粒体抗体M2（AMA-M2）和免疫球蛋白M（IgM）的水平。此外，DNT对肝脏T细胞表现出强烈的杀伤作用并强烈抑制其增殖，但未显著改善PBC肝脏的组织学。然而，DNT与口服UDCA联合治疗主要改善了肝脏炎症并显著抑制了肝脏T和B细胞。体外进一步研究表明，UDCA上调了DNT的增殖，增加了功能分子穿孔素的表达，并通过法尼醇X受体（FXR）/JNK信号通路降低了小鼠和人DNT中NKG2A和内皮细胞蛋白C受体（EPCR）的表达。
单次转移DNT可改善小鼠的PBC，而DNT与口服UDCA联合治疗显示出更好的疗效，对肝脏T和B细胞的抑制作用更强。本研究突出了基于DNT的联合治疗在PBC中的潜在应用，特别是对于UDCA无反应者。
