Checkpoint Inhibitors to Restore Monocyte/Macrophage Function in Liver Failure

肝功能衰竭可能发生在以前肝脏健康的人(急性肝功能衰竭)或肝硬变患者(急性失代偿)。无论原因如何，肝功能衰竭都是一种严重的医疗紧急情况，可能会进展到其他器官(包括肾、心、肺和脑)衰竭和死亡。肝功能衰竭患者由于免疫系统功能丧失，极易受到感染。感染会使肝功能衰竭恶化，并增加死亡的风险。我们最近在一种肝功能衰竭的动物模型中发现了免疫功能下降的原因之一。在该模型中，驻留在肝脏的免疫细胞称为巨噬细胞，而它们的循环对应细胞单核细胞无法清除血液中的细菌。因此，这种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的药物来逆转免疫缺陷，这种药物目前被用于治疗某些类型的癌症。我们有初步证据表明，在肝功能衰竭患者中，巨噬细胞和单核细胞也会出现同样的问题。这项研究计划旨在调查尼沃卢单抗是否能够逆转肝功能衰竭患者的免疫缺陷。当务之急将是确定尼伏卢单抗在肝功能衰竭患者中的安全性。尼伏鲁单抗已被证明可引起少数患者的肝脏炎症，这可能会加剧肝功能衰竭。然而，尼伏鲁单抗被反复用于癌症患者，而我们只建议使用单次剂量。为了评估安全性，我们会给少量患者服用小剂量的尼伏卢单抗，并仔细观察6个月。为了证明尼伏卢单抗能恢复免疫功能，我们将仔细检查治疗前后血液中的单核细胞。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找到，而且在肝脏还在体内的情况下，无法测试它们的功能。除了测试尼伏卢单抗的免疫反应外，我们还希望调查这种治疗是否降低了感染的风险。肝衰竭患者总是受到密切的感染监测，因此我们将能够衡量与我们通常预期的感染率相比，治疗后的感染率是否有所下降。有一种蛋白质(Spd-L1)从免疫细胞释放到血液中，似乎是免疫功能障碍的有力指标。检测这种蛋白比检测单核细胞的功能容易得多，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受益于尼伏卢单抗治疗。如果这些研究成功，我们有望利用它们来指导临床试验的设计，以测试尼伏卢单抗是否可以用于肝功能衰竭患者的治疗

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