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

GSK已经开发出一种用于治疗的单克隆抗体，可以从体内去除活化的免疫细胞（称为T细胞），这些细胞在许多自身免疫性疾病中很重要。这些活化的T细胞，可以引起炎症，在它们的表面上有一种叫做LAG 3的分子。据报道，LAG 3也由另一种可以抑制炎症的T细胞表达，称为调节性T细胞。事实上，LAG 3在T细胞上的作用还不清楚。该提案的目的是告知决定这种抗体是否可用于治疗系统性红斑狼疮（SLE）患者。系统性红斑狼疮是一种自身免疫性疾病，主要影响育龄妇女，可导致严重的疾病，甚至过早死亡。这种情况几乎没有治疗方法，患者通常不得不依赖于使用类固醇，这具有严重和显著的副作用。已知活化和调节性T细胞在SLE中是异常的，并且可能导致疾病。我们将确定LAG 3在血液和尿液中活化和调节性T细胞上的分布，后者反映了SLE患者肾脏中常受SLE影响的T细胞。我们这样做是因为重要的是，我们不会通过使用这种抗体治疗患者来引起更多的炎症，如果表面上有LAG 3的细胞中有很大一部分试图抑制，而不是引起，接下来我们将添加消耗性抗-LAG 3抗体从SLE患者的血液中提取细胞，看看总体效果是减少还是增加炎症。我们将测量T细胞的活化状态，无论是活化的还是调节性T细胞从培养物中去除，以及这如何影响引起炎症的细胞因子的产生。我们将评估这些实验的结果，以决定是否使用这种抗LAG 3抗体进行临床试验，如果该提议的结果令人鼓舞，即抗LAG 3去除引起炎症的T细胞，但不去除免疫抑制调节性T细胞，这将是下一步。该临床试验将与其他EMINENT中心合作，并将在该项目完成后考虑资助。

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.