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

Henry Barrett, Lesley Smyth†, Charlotte Hulme, Marcelo Andrade De Lima, Aled Clayton*, Roshan Amarasena and Oksana Kehoe

†University of East London, *Cardiff University

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.

One promising alternative to traditional treatments is to treat patients with immunosuppressive cells like T regulatory cells (Tregs) – see Figure 1. These cells are taken from a patient, cultured and reintroduced back into their system. Recent clinical trials have demonstrated that Treg therapies are safe and cause minimal side effects when used to manage organ transplants and autoimmune disorders like type 1 diabetes. One way these cells keep the immune response in check is by releasing extracellular vesicles (EVs). These small bubble[1]like structures are made of a cells membrane and contain messenger molecules that calm other immune cells down. As they play such a large role in Treg function, these EVs may be able to treat patients in the same way as Tregs. Although both approaches need more study, Treg-derived EVs may be a cheaper and easier to produce, could be easier to ship and store and may be able to treat people other than the original donor. Overall, EVs have the potential to be a more accessible treatment than Treg cell therapy.

At the RJAH, we are comparing Treg-derived EVs taken from healthy volunteers to those taken from people with rheumatoid arthritis. Specifically, we are comparing what messenger molecules are found on these EVs, alongside how well they suppress immune cells. To do this, Tregs will be isolated from blood samples using magnetic cell labelling and then stimulated to produce EVs. Immune cells, specifically T effector cells, will then be treated with varying doses of Treg-derived EVs to see how they change the T effector cells response to inflammatory signals. Finally, both the surface of these Treg-derived EVs and their content will be analysed and compared.

Ultimately, we hope that this project will improve our understanding of how Tregs work, will show if rheumatoid arthritis effects EV composition and suppressive capacity and if EVs from healthy donors would be better treatments than EVs made from a patient’s own cells.