A mechanistic evaluation of gliflozins in CD4+ T cells and their repurposing in T cell-mediated autoimmunity

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An overactive immune system is the cause of autoimmune conditions such as rheumatoid arthritis and systemic lupus erythematosus (lupus). Autoimmunity is where the body's own immune cells, called T-cells, attack healthy tissues and organs. Most autoimmune conditions have no cure and current therapies are not always effective, leaving many patients with debilitating symptoms that severely restrict their quality of life. In this proposal, we will examine whether a group of drugs called gliflozins could be used to treat autoimmune diseases. Gliflozins are a safe and clinically approved drug class currently used to treat type 2 diabetes because they control blood-sugar levels. Some gliflozins have additional effects and disrupt the way our cells metabolise fuels from our diet such as sugar and protein. Autoimmune T-cells adapt their metabolism - the way in which they take up and process sugar and protein and this helps them attack the body's healthy tissues and organs.By affecting the ways in which our T-cells process nutrients, we reason that certain gliflozins could work as a treatment for autoimmunity. We will carry out this research in three stages - first by using T-cells from healthy donors' blood, secondly by testing the drugs on T-cells obtained from rheumatoid arthritis and lupus patients amongst others, and finally seeing how the drugs work in a mouse model of autoimmunity. If this research confirms our thinking, these results will inform the design of a clinical trial of gliflozins for treatment of autoimmunity, with the goal of improving outcomes in people with autoimmunity. Since gliflozins are already prescribed safely for other purposes, these benefits could potentially reach patients relatively rapidly. The research will be carried out at Swansea University Medical School, where specialists in human immune cells will collaborate with scientists at the University of Bristol, the Francis Crick Institute and University College London. We will do this work in the laboratory by testing the metabolism and function of T-cells exposed to gliflozins in multiple autoimmune diseases (rheumatoid arthritis and lupus).Our ultimate aim is to enable the development of improved treatments for people with autoimmune disorders by better understanding how gliflozins might affect T-cell activity, and in particular by determining the effects of different types of gliflozins.