Investigating the role of LAG3 in regulatory and effector T cells in systemic lupus erythematosus

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GSK have developed a monoclonal antibody for therapy that removes activated immune cells (called T cells), which are important in many autoimmune diseases, from the body. These activated T cells, which can cause inflammation, have a molecule on their surface called LAG3. LAG3 has also been reported to be expressed by another T cell which can suppress inflammation called regulatory T cells. In fact, the role of LAG3 on T cells is not well understood. The aim of this proposal is to inform a decision as to whether this antibody could be used to treat patients with systemic lupus erythematosus (SLE). SLE is an autoimmune disease, predominantly affecting women of child-bearing age, which can cause serious disease and even early death. There are few treatments available for this condition, and patients often have to rely on the use of steroids, which have serious and significant side effects. Both activated and regulatory T cells are known to be abnormal in SLE and could contribute to disease. We will determine the distribution of LAG3 on activated and regulatory T cells in the blood and urine, the latter reflects the T cells in the kidney often affected in SLE, in patients with SLE. We are doing this because it is important we do not cause more inflammation by using this antibody to treat patients, which might happen if a significant proportion of those cells that have LAG3 on their surface are trying to suppress, rather than cause, inflammation.We will next add the depleting anti-LAG3 antibody to cells taken from the blood of patients with SLE to see whether the overall effect is to reduce or increase inflammation. We will measure the activation status of the T cells, whether activated or regulatory T cells are removed from the cultures, and how this affects the production of inflammation causing cytokines. We will assess the results of these experiments to decide whether to proceed to a clinical trial using this anti-LAG3 antibody, which will be the next step if the results from this proposal are encouraging i.e. anti-LAG3 removes T cells causing inflammation but not immune suppressing regulatory T cells. This clinical trial will be in collaboration with other EMINENT centres and will be considered for funding after this project has completed.