THE POTENTIAL UTILITY OF HUMAN REGULATORY T CELL-DERIVED EXTRACELLULAR VESICLES TO CONTROL INFLAMMATION IN RHEUMATOID ARTHRITIS (VERSUS)

Henry Barrett, Lesley Smyth†, Charlotte Hulme, Roshan Amarasena and Oksana Kehoe

†University of West London

Funded by the Orthopaedic Institute and Keele University

Rheumatoid arthritis is an autoimmune disorder effecting just under 1% of the population. It causes swelling and inflammation within the joints which leads to joint damage, mobility issues, pain and fatigue. Additionally, 20% of patients are out of work within 2 years of diagnosis leading to further financial and psychological challenges. Although current treatments are available, they aren’t always effective and can come with unpleasant side effects. This leads to over 75% of people being taken off first line treatments within a year of starting them.

Our lab works with the goal of finding alternative treatments for rheumatoid arthritis (RA), looking to prevent the inappropriate activation of immune responses before they can harm patients. One promising approach is to treat patients with cells able to suppress immune responses, in this case regulatory T cells (Tregs). These cells have shown promise within clinical trials treating other autoimmune disorders like Crohn’s disease and type 1 diabetes, with a recent RA clinical trial involving modified Tregs starting in 2025.

Despite their promise, cell therapies will be difficult to introduce into the clinic for routine use. The need to use a patient’s own cells makes treatments hard to produce on mass and creates an inherently variable treatment which is hard to regulate. The need to manufacture cells at the correct time, then store and ship them in a way that keeps them alive makes distributing treatments logistically challenging. Additionally, the ability for cells to adapt to their environment leaves treatments potentially less stable within the body than traditional drugs.

Our lab believes that extracellular vesicles (EV) are the solution to these problems. These nanosized structures are released by cells to communicate, as Tregs are telling immune cells not to react, Treg-EVs could be used to prevent unwanted immune responses. This means that Treg-EVs could be used to manage autoimmune disorders like RA while avoiding the challenges associated with cell therapies.

This project has managed to isolate Tregs from blood donated by RA patients and healthy volunteers, successfully expand them and isolate Treg-EVs from these cells (Figures 1 & 2). We have studied the impact of RA and cell culture on Treg biomarker expression and the impact of RA on Treg functionality.

We also explored the impact of RA on Treg-EVs lipid composition (Figure 3). Ultimately, we hope that this project will improve our understanding of how Tregs work and will show if rheumatoid arthritis effects EV composition and suppressive capacity.