Autologous Macrophage Therapy for Liver Cirrhosis

自体巨噬细胞治疗肝硬化

• 批准号: MR/M007588/1
• 负责人: Stuart Forbes
• 金额: $ 390.62万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM007588%2F1
• 关键词: Autologous; Macrophage; Therapy; Liver; Cirrhosis

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.

肝硬化是一种常见的疾病，其原因包括病毒性肝炎、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，晚期肝硬化最终导致肝功能衰竭和死亡。在英国，肝硬化的死亡率正在迅速上升。终末期肝病唯一成功的治疗方法是肝移植，但除了手术本身的风险外，这还有几个问题：器官供应有限，不幸的是，患者经常在合适的器官可用之前死于肝移植等待名单。移植的其他问题是免疫抑制增加了肾衰竭、癌症和严重感染的风险。肝硬化的严重程度可以使用简单的数值评分来测量，例如MELD和UKELD评分。这些评分预测未来死于肝硬化的风险，并用于评估和优先考虑患者是否需要肝移植。正常的肝脏在短期损伤后具有惊人的再生能力，并且可以通过肝脏中的细胞如肝细胞和胆管上皮细胞的分裂有效地实现这一点。肝硬化的一个标志是肝脏中疤痕组织的沉积增加，这与其他因素结合，降低了肝脏再生的能力。我们几年来的研究表明，如果对肝脏的有害损害被去除，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。这个恢复阶段是协调的，并在很大程度上通过称为巨噬细胞的细胞的作用来实现。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瘢痕组织，刺激肝脏自身的干细胞扩增和繁殖并最终帮助这些干细胞通过分泌几种因子转变为肝细胞非常重要。我们已经利用巨噬细胞的这些特征开发了一种治疗肝硬化的细胞疗法，我们希望首次在人类中进行临床试验。我们已经在小鼠肝纤维化模型中表明，注射实验室中从骨髓中生长的巨噬细胞能够显着减少瘢痕形成并改善再生和肝功能。我们继续对从健康志愿者和肝硬化患者中分离的人类细胞进行研究。在这里，我们可以从患者血液中分离出大量的单核细胞，并在1周内将它们转化为与小鼠细胞具有相似特性的巨噬细胞。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并增加肝再生。在这笔赠款中，我们正在寻求将这些令人鼓舞的结果转化为肝硬化患者的治疗方法。肝硬化患者将使用细胞分离机分离单核细胞，这需要2至4小时。将单核细胞分成3部分，冷冻备用。根据需要，冷冻的单核细胞将被解冻并分化为巨噬细胞。在密切监测下，将巨噬细胞重新输注到3组（每组3例）患者中，细胞数量增加至1亿个细胞。如果该单次给药耐受性良好，我们将在15名单独的患者中进行重复输注研究。在该研究中，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。患者将定期接受长达1年的定期血液检查，超声扫描和MRI扫描，这将告诉我们肝脏的功能如何。如果这项首次人体研究成功，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研究中心进行该研究。

项目成果

Phenotypic and functional characterization of macrophages with therapeutic potential generated from human cirrhotic monocytes in a cohort study.

• DOI: 10.1016/j.jcyt.2015.07.016
• 发表时间: 2015-11
• 期刊: Cytotherapy
• 影响因子: 4.5
• 作者: Moore JK;Mackinnon AC;Wojtacha D;Pope C;Fraser AR;Burgoyne P;Bailey L;Pass C;Atkinson A;Mcgowan NW;Manson L;Turner ML;Campbell JD;Forbes SJ
• 通讯作者: Forbes SJ

Study protocol: a multicentre, open-label, parallel-group, phase 2, randomised controlled trial of autologous macrophage therapy for liver cirrhosis (MATCH).

• DOI: 10.1136/bmjopen-2021-053190
• 发表时间: 2021-11-08
• 期刊: BMJ open
• 影响因子: 2.9
• 作者: Brennan PN;MacMillan M;Manship T;Moroni F;Glover A;Graham C;Semple S;Morris DM;Fraser AR;Pass C;McGowan NWA;Turner ML;Lachlan N;Dillon JF;Campbell JDM;Fallowfield JA;Forbes SJ
• 通讯作者: Forbes SJ

Development, functional characterization and validation of methodology for GMP-compliant manufacture of phagocytic macrophages: A novel cellular therapeutic for liver cirrhosis.

GMP兼容吞噬巨噬细胞生产的方法的发展，功能表征和验证：一种新型的细胞肝硬化细胞治疗。

• DOI: 10.1016/j.jcyt.2017.05.009
• 发表时间: 2017-09
• 期刊: Cytotherapy
• 影响因子: 4.5
• 作者: Fraser AR;Pass C;Burgoyne P;Atkinson A;Bailey L;Laurie A;W A McGowan N;Hamid A;Moore JK;Dwyer BJ;Turner ML;Forbes SJ;Campbell JDM
• 通讯作者: Campbell JDM