Understanding T cell immunity in anti-NMDAR encephalitis: Developing therapeutic tools for neurological autoimmunity.

点击翻译按钮获取中文摘要

Encephalitis (inflammation of the brain) affects 6000 people in the UK annually. It commonly causes significant disability, including seizures, memory problems, loss of independence and unemployment all of which affect families and carers of patients. While many cases are caused by infection, a large number occur as a result of abnormal immune responses, where cells of the immune system produce antibodies, which attack specific proteins on the surface of healthy brain cells. Currently, while we have some available treatments for immune-mediated encephalitis, often patients are resistant to treatment, respond poorly and need to remain in hospital for several months either on a specialist ward or the intensive care unit. There is a pressing need to understand how and why immune-mediated encephalitis occurs, and to identify new forms of treatment to improve recovery and outcomes for our patients. It is not known what triggers the generation of autoantibodies that cause encephalitis, but recent evidence has suggested an important role for a specific type of immune cell (T cells) in their generation. In addition, it has recently been observed that some new cancer treatments called 'checkpoint inhibitors' or more generally, 'cancer immunotherapy', which work by affecting T cell function, can cause immune-mediated encephalitis and other immune-mediated neurological complications. These checkpoint inhibitors make normal T cells attack cancer cells more aggressively, but unfortunately, as a side effect, unregulated T cells can cause autoimmunity and also damage healthy body cells including cells in the brain. The proposed project has 2 broad aims: (i) to characterise the function of T cell responses in patients with immune mediated encephalitis and with neurological complications after checkpoint inhibitor therapy; and (ii) to use state of the art genetic engineering to develop targeted immune suppressive therapies by generating regulatory immune cells (Tregs), which can be activated within the brain to suppress inflammation regardless of it's cause. For the first aim we will examine the number and function of T cells in healthy volunteers and in patients and investigate whether it is easier to trigger unwanted T cell responses to specific brain proteins (NMDAR peptides) in patients who develop encephalitis and NMDAR autoantibodies.For the second aim we will explore the use of gene-engineered T cells in the treatment of immune-mediated encephalitis. While some T cells have an 'attack' function, such as those causing disease, others (Regulatory T cells, or Tregs) are immune regulators and can suppress inflammation. We will use state-of-the-art genetic engineering to generate T regs which can become activated on entry into the brain, and switch off abnormal inflammation. Designing a personalised, precision-targeted cellular therapy for encephalitis, could transform the way we think about treating not just encephalitis, but a range of other inflammatory diseases of the brain, such as multiple sclerosis.Over the last 15 years, University College London has been at the forefront of T cell engineering and now has the largest clinical translation pipeline of genetically engineered immune cells in Europe. Recently gene-engineered T cells have been introduced as a licensed treatment for childhood leukaemias. In the brain, they are also being trialled in patients with glioblastoma, a type of brain tumour. We aim to complete pre-clinical testing of these cells in the laboratory. If successful this could pave the way for a phase I clinical trials in the next 3-5 years.