Autologous Macrophage Therapy for Liver Cirrhosis

肝硬变是一种常见疾病，由多种原因引起，包括病毒性肝炎、肥胖、酗酒、遗传性肝病和免疫系统功能障碍。无论肝损伤的原因是什么，进展期肝硬变最终都会导致肝功能衰竭和死亡。在英国，死于肝硬变的发病率正在迅速上升。终末期肝病的唯一成功治疗方法是肝移植，但除了手术本身的风险外，这还存在几个问题：器官供应有限，不幸的是，患者经常在合适的器官可用之前屈从于肝脏移植的等待名单。移植的其他问题是免疫抑制会增加肾衰竭、癌症和严重感染的风险。肝硬变的严重程度可以用MELD和UKELD评分等简单的数字评分来衡量。这些评分预测未来死于肝硬变的风险，并被用来评估和优先考虑肝移植患者的需求。正常肝脏在短期损伤后具有令人难以置信的再生能力，并可通过肝细胞和胆管上皮细胞等肝细胞的分裂有效地完成这一任务。肝硬变的一个特点是肝脏中的疤痕组织沉积增加，这与其他因素结合在一起降低了肝脏再生的能力。我们几年来的研究表明，如果去除对肝脏的伤害，例如通过治疗病毒感染或炎症，那么肝脏可以在一定程度上再生。这一恢复阶段在很大程度上是通过被称为巨噬细胞的细胞的作用来协调和实现的。我们已经证明，当慢性损伤的肝脏正在进行修复和再生时，巨噬细胞对于减少肝脏中的疤痕组织，刺激肝脏自身的干细胞扩张和增殖，最终通过分泌几种因子帮助这些干细胞转化为肝细胞是重要的。我们已经利用巨噬细胞的这些特征开发了一种治疗肝硬变的细胞疗法，我们希望将其用于人类的首次临床试验。我们已经在小鼠肝纤维化模型上表明，注射实验室培养的骨髓巨噬细胞能够显著减少瘢痕形成，改善再生和肝功能。我们继续用从健康志愿者和肝硬变患者身上分离出来的人类细胞进行研究。在这里，我们可以从患者的血液中分离出大量的单核细胞，并将它们转化为巨噬细胞，在一周内具有与小鼠细胞相似的特性。我们已经在肝损伤模型中测试了这些细胞，它们还可以减少纤维化和促进肝再生。在这笔赠款中，我们正寻求将这些令人鼓舞的结果转化为对肝硬变患者的治疗。肝硬变患者将使用细胞分离机分离单核细胞，这需要2到4个小时。单核细胞将被分成3部分，冷冻后供以后使用。按照要求，冷冻的单核细胞将解冻并分化为巨噬细胞。巨噬细胞将在3组患者的密切监测下重新输注，使用的细胞数量增加到1亿个。如果这种单次剂量耐受性良好，我们将在15名单独的患者中进行重复输液研究。在这项研究中，患者将在单核细胞分离后8、30和60天接受3次巨噬细胞输注。患者将被定期观察长达一年的时间，定期进行血液测试、超声波扫描和一种核磁共振扫描，以告诉我们肝脏功能的良好程度。如果这项首个人的研究成功，我们将计划扩展到一项随机研究，我们将计划在英国的其他地点进行。

Liver cirrhosis is a common disease that is due to many causes including viral hepatitis, obesity, alcohol abuse, genetic liver disease, and immune system dysfunction. Regardless of the cause of the liver injury advanced liver cirrhosis results eventually in liver failure and death. The incidence of deaths from liver cirrhosis is rising rapidly in the UK. The only successful treatment for end stage liver disease is liver transplantation but this has several problems in addition to the risk from the operation itself: Organ supply is limited and patients unfortunately frequently succumb on the liver transplant waiting list before a suitable organ becomes available. Other problems with transplantation are that immunosuppression increases the risk of renal failure, cancer and severe infections. The severity of liver cirrhosis can be measured using simple numerical scores such as the MELD and UKELD scores. These scores predict the future risk of death from liver cirrhosis and are used to assess and prioritise a patients need for liver transplantation. The normal liver as an incredible capacity to regenerate following short term damage and can accomplish this efficiently through division of the cells in he liver such as hepatocytes ad biliary epithelial cells. A hallmark of cirrhosis is that here is an increased deposition of scar tissue in the liver and this combines with other factors to reduce the livers ability to regenerate. Our research over several years has shown that if the injurious insult to the liver is removed, for example by treating a viral infection or inflammatory condition then the liver can regenerate to a degree. This recovery phase is coordinated ad achieved in large part through the action of cells termed macrophages. We have shown that when the chronically damaged liver is undergoing repair and regeneration the macropahges are important for reducing the scar tissue in the liver, stimulating the livers own stem cells to expand and multiply and finally help those stem cells turn into hepatocytes through the secretion of several factors. We have exploited these features of the macrophage to develop a cell therapy for liver cirrhosis that we would like to take forward for a clinical trial in man for the first time. We have shown in mouse model of liver fibrosis that the injection of macrophages, grown in the lab from bone marrow, is able to reduce significantly the scarring and improve regeneration and liver function. We have gone on to perform studies with human cells isolated from healthy volunteers and patients with liver cirrhosis. Here we can isolate large amounts of monocytes from patients blood and turn them into macrophages that have similar properties to the mouse cells over a 1 week period. We have tested these cells in models of liver injury and they also reduce fibrosis and increase liver regeneration. In this grant we are seeking to turn these encouraging results into a treatment for patients with cirrhosis. Cirrhotic patients will have monocytes isolated using a cell separator machine which takes 2 to 4 hours. The monocytes will be split into 3 parts which will be frozen for later use. As required the frozen monocytes will be defrosted and differentiated into macrophages. The macrophages will be re-infused under close monitoring in 3 groups of 3 patients using increasing cell numbers up to 100 million cells. If this single dose is well tolerated we will perform, in 15 separate patients a repeat infusion study. in this study patients will receive 3 macrophage infusions of cells at 8, 30 and 60 days post monocyte isolation. Patients will be observed regularly for up to 1 year with regular blood test, ultrasound scans and a type of MRI scan that will tells us how well the liver is functioning. If this first in man study is successful and we would plan to extend to a randomized study which we would plan to conduct across other sites in the UK.