Stable Functional induced regulatory T cells (SFiTregs) for the treatment of Primary Biliary Cholangitis

Primary biliary cholangitis (PBC) is a lifelong autoimmune disease affecting around 22,000 people in the UK, 90% of whom are women. Autoimmune diseases like PBC arise from aberrant immune responses, leading to organ damage. In PBC, the immune system’s T cells target and attack the liver’s bile ducts, leading to progressive bile duct injury and liver scarring, preventing bile drainage from the liver and causing symptoms of itch, fatigue and jaundice. The only available treatment for PBC is ursodeoxycholic acid. Another drug, obeticholic acid, was introduced but was withdrawn in June 2024 by authorities due to a lack of efficacy. Both drugs target bile acids, rather than the underlying autoimmune cause. Unfortunately, only 60% of patients respond to present treatments, leaving patients susceptible to an increasingly intractable itch and profound fatigue, impacting daily activities and eroding quality of life. As PBC progresses, a liver transplant becomes necessary. Autoimmune liver diseases like PBC now make up over a quarter of liver transplants, an already scarce resource. Even then, in over a third of patients, PBC recurs, necessitating re-transplantation. Normally, regulatory T cells (Tregs), another kind of immune cell, protect against autoimmune attacks like that seen in PBC. Tregs educate the immune system to stop and prevent autoimmune attacks. Infusing Tregs has even been shown to treat PBC in mice, returning them to health. Many have tried to use Tregs to treat various human autoimmune diseases. However, there are few Tregs in human blood, and when grown in the lab, Tregs can be unstable, making their manufacture challenging. Due to this, to date, Tregs have not shown efficacy as a treatment for human autoimmune diseases. Having first discovered Tregs in 1995, Shimon Sakaguchi’s laboratory published a new method of Treg generation in 2019, producing stable, highly functional Tregs (SFiTregs). This method generates large numbers of cells in a short period. Last year, I spent three months in Shimon Sakaguchi’s laboratory, learning this novel technique and generating SFiTregs from the blood of PBC patients, becoming the first to generate SFiTregs for application in human disease. Through this fellowship, I will generate SFiTregs and investigate their efficacy and function in PBC. As Europe’s largest solid organ transplant unit, we receive a large number of livers for research, including approximately 30 PBC explants per year, made available through established ethics. Perfusing PBC livers with generated SFiTregs, I aim to observe their migration and localisation using microscopy, determining the ability of SFiTregs to reach the site of tissue damage in PBC. I will also explore whether SFiTregs can survive and function in inflammatory environments and examine whether they can prevent bile duct damage. This will be done through cell culture experiments with fresh human liver cells from our transplant programme. By conducting the above work, I aim to demonstrate a novel, superior method of Treg generation with utility in PBC, a typical autoimmune disease. This would introduce a new therapeutic option for PBC, relieving patients from a poor quality of life hampered by intractable itch, fatigue, jaundice, and the need for transplantation. Success in the project would pave the way for further application of SFiTregs. Both organ transplantation and autoimmune diseases are in need of new, effective treatments, and with this project’s success, we may see a new era in immune therapies, defined by SFiTregs.