24-Nor-ursodeoxycholic acid: a novel treatment targeting T-cell-mediated immune dysregulation in primary sclerosing cholangitis and beyond

Abstract

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterised by progressive inflammation and fibrosis of the bile ducts, leading to biliary cirrhosis and an increased risk of cholangiocarcinoma. PSC is commonly associated with inflammatory bowel disease (IBD). The pathogenesis of PSC is complex and not fully understood, but immune-mediated mechanisms, particularly T cell involvement, are believed to play a central role. Genetic studies have identified associations between PSC susceptibility and specific human leucocyte antigen (HLA) haplotypes, suggesting a role for T cell-mediated autoimmunity.1 Gut and liver resident T cells from PSC patients with concurrent IBD exhibit heightened responses to shared antigens, indicating a related pathogenesis between PSC and IBD.2 Peripheral blood mononuclear cells from PSC patients show increased frequencies of T helper 17 (Th17) and Th1/Th17 cells on pathogen stimulation.3 Within the liver, there is an accumulation of tissue-resident naïve-like CD4+ T cells predisposed to differentiate into Th17 cells. These tissue-resident T cells produce interleukin (IL)−17 and IL-22, contributing to local inflammation by recruiting neutrophils via CXCL8.4 Therefore, restoring immune balance in PSC represents a promising therapeutic approach. However, while existing immune-modulating therapies showed some improvement in cholestasis markers, particularly in PSC patients with worse liver function, the overall clinical benefits were limited. 24-Nor-ursodeoxycholic acid (NorUDCA) is …