Checkpoint Inhibitors to Restore Monocyte/Macrophage Function in Liver Failure

肝功能衰竭可能发生在先前肝脏健康的人（急性肝功能衰竭）或肝硬化患者（急性代偿失代偿）。无论病因如何，肝功能衰竭都是一种严重的医疗紧急情况，可能会发展为其他器官（包括肾脏、心脏、肺和大脑）衰竭和死亡。由于免疫系统功能丧失，肝功能衰竭的患者非常容易受到感染。感染会加重肝功能衰竭，增加死亡风险。我们最近在肝衰竭的动物模型中发现了免疫功能降低的原因之一。在这个模型中，驻留在肝脏中的免疫细胞，称为巨噬细胞，以及它们的循环对应体，单核细胞，不能清除血液中的细菌。因此，细菌能够在全身传播并引起感染。在这个模型中，我们能够使用一种名为Nivolumab的药物逆转免疫缺陷，这种药物目前用于治疗某些类型的癌症。我们有初步证据表明，巨噬细胞和单核细胞同样的问题也发生在肝功能衰竭患者身上。该研究计划旨在调查Nivolumab是否能够逆转肝衰竭患者的免疫缺陷。首要任务将是确定Nivolumab在肝功能衰竭患者中的安全性。Nivolumab已被证明在少数患者中引起肝脏炎症，这可能会加剧肝衰竭。然而，Nivolumab是反复给予癌症患者，而我们只建议使用单一剂量。为了评估安全性，我们将给少数患者小剂量的Nivolumab，并对他们进行6个月的仔细随访。为了证明Nivolumab可以恢复免疫功能，我们将在治疗前后仔细检查血液中的单核细胞。虽然我们也想看看巨噬细胞的功能，但这是不可行的，因为它们只能在肝脏组织中发现，而且当肝脏还在体内时，它们的功能无法测试。除了测试对Nivolumab的免疫反应外，我们还希望研究这种治疗是否能降低感染的风险。肝功能衰竭的患者总是处于密切的感染监测之下，因此我们将能够衡量，与我们通常预期的感染率相比，治疗是否降低了感染率。有一种蛋白质（sPD-L1）从免疫细胞释放到血液中，这似乎是免疫功能障碍的一个强有力的指标。测量这种蛋白比检查单核细胞的功能要容易得多，因此我们建议探索sPD-L1水平是否会告诉我们哪些患者可能从Nivolumab治疗中受益。如果这些研究是成功的，我们期望用它们来指导临床试验的设计，以测试Nivolumab是否可以作为肝衰竭患者治疗的一部分

Liver failure may occur in people with previously healthy livers (acute liver failure) or in patients with cirrhosis (acute decompensation). Irrespective of the cause, liver failure is a serious medical emergency which may progress to failure of other organs (including the kidneys, heart, lungs and brain) and death. Patients with liver failure are incredibly susceptible to infection due to loss of function in their immune system. Infection makes the liver failure worse and increases the risk of dying. We have recently found one of the causes of reduced immune function in an animal model of liver failure. In the model immune cells resident in the liver, called macrophages, and their circulating counterparts, monocytes, are unable to clear bacteria from the blood. The bacteria are therefore able to disseminate throughout the body and cause infection. In the model we were able to reverse the immune defect using a drug called Nivolumab which is currently used to treat some types of cancer. We have preliminary evidence that the same problem with macrophages and monocytes occurs in patients with liver failure. This programme of research sets out to investigate whether Nivolumab is able to reverse the immune defect seen in patients with liver failure. The first priority will be to establish the safety of Nivolumab in patients with liver failure. Nivolumab has been shown to cause liver inflammation in a minority of patients which could potentially exacerbate liver failure. However, Nivolumab is given repeatedly for patients with cancer whereas we only propose to use a single dose. In order to assess safety we will give a small number of patient a small dose of Nivolumab and follow them carefully for 6 months. In order to demonstrate that Nivolumab restores immune function we will carefully examine monocytes from blood before and after treatment. Although we would also like to look at the function of the macrophages, this is not feasible as they can only be found in liver tissue and their function cannot be tested whilst the liver is still in the body. In addition to testing the immune response to Nivolumab we also wish to investigate whether this treatment reduces the risk of infection. Patients with liver failure are always kept under close surveillance for infection so we will be able to measure whether the rate of infection is reduced by treatment compared to the rate of infection that we would normally expect. There is a protein (sPD-L1) released into the blood from immune cells which appears to be a strong indicator of immune dysfunction. It is a lot easier to measure this protein than to examine the function of monocytes so we propose to explore whether sPD-L1 levels will tell us which patients might benefit from treatment with Nivolumab.If these studies are successful we would expect to use them to inform the design of a clinical trial to test whether Nivolumab could be used as part of the treatment for patients with liver failure