Alpha-1 antitrypsin to improve the efficacy of hepatocyte transplantation in children with liver-based metabolic disease

Alpha-1抗胰蛋白酶提高肝代谢疾病儿童肝细胞移植的疗效

• 批准号: MR/P026699/1
• 负责人: Anil Dhawan
• 金额: $ 107.7万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP026699%2F1
• 关键词: Alpha; antitrypsin; improve; efficacy; hepatocyte

Hepatocyte (Liver cell) transplantation is an alternative to liver transplantation for certain conditions. It involves the transplantation of the cells into the patient's liver, usually via the main vein supplying the liver, in a minimally invasive way. Patients for whom this treatment is especially suitable are those who are missing a particular enzyme which is made in the liver cell. This leads to buildup of toxic waste products and consequent irreversible brain injury. Two such conditions: Crigler-Najjar syndrome (where bilirubin cannot be broken down), and the urea cycle defects (where ammonia is not eliminated), cause profound brain injury due to accumulation of these toxic compounds. Replacing the whole liver, to replace the missing enzyme, is an option but comes at a high price as this involves major surgery, often with complications, a prolonged hospital stay, and leaves no fallback if the transplant fails. Furthermore, the donor organ pool is particularly small for children, who will need part of an adult liver. Thus the wait for a suitable organ may be years for children who have an extremely poor quality of life and with the potential to develop a metabolic 'crisis' at any point in time. In addition, they only actually need a fraction of liver in order to correct the deficiency. There is thus a redundancy in replacing a whole liver, particularly in view of the restricted resource and large demand. Hepatocytes are isolated from livers that don't meet the criteria for organ transplantation, and so they are an excellent use of an otherwise unusable resource. They can be frozen and stored and thus are available off the shelf. Hepatocyte transplantation also allows the patients own liver to be preserved while providing 10-15% of the liver function, i.e. sufficient function from the otherwise deficient enzyme to correct the disease. We know that, at time of infusion into the portal vein, the cells encounter attack from the innate immune system: blood begins to clot, proteins are released, attracting the defence cells of the body, and hepatocytes are destroyed before they can reach the liver to engraft and settle. Conventional immuno-suppression including steroids doesn't allow to overcome this and so, more than ninety percent of cells are destroyed before they have the opportunity to engraft. Alpha-1 antitrypsin (AAT) is a protein made in liver cells and has a range of effects which can block a lot of the adverse effects of inflammation without the side effects of most conventional immunosuppressants, which leave the body vulnerable to attack from infection and cause poor wound healing. AAT is used in clinical trials world-wide, in a variety of conditions which are influenced by inflammation such as type 1 diabetes and ischaemic heart disease. Considerable success of AAT as an immune system modifier has also been seen in the field of islet transplantation in patients with diabetes, where these insulin producing cells are also transplanted into the liver. We wish to test the use of AAT in the field of hepatocyte transplantation as we believe that it will lead to improved engraftment of cells in the liver and thus, better medium- to long-term function of the cells, making a significant difference to those treated. We predict that the mechanism through which this occurs will be the suppression of the innate (immediate) immune system and we will measure both the function of the cells in terms of supplying the missing enzyme as well as the effect that AAT has on the immediate immune response once these cells are infused. Though hepatocyte transplantation is a small field, it can result in life-changing treatment for children with devastating liver-based disease. Should we demonstrate the success of this therapy using AAT, this will give further credence to the use of AAT as an effective and safe immuno-modulator, in the context of transplantation in general, and in other inflammatory conditions.

在某些情况下，肝细胞（肝细胞）移植是肝移植的替代方法。它涉及细胞将细胞移植到患者的肝脏中，通常是通过最低侵入性的主要静脉提供肝脏的主要静脉。这种治疗特别合适的患者是缺少在肝细胞中制造的特定酶的患者。这会导致有毒废物的积累，并导致不可逆转的脑损伤。有两个这样的条件：Crigler-Najjar综合征（胆红素不能分解），尿素周期缺陷（未消除氨），由于这些有毒化合物的积累而导致严重的脑损伤。取代整个肝脏，以取代缺失的酶，是一种选择，但价格高昂，因为这涉及重大手术，通常会发生并发症，长时间住院时间，如果移植失败，则不会退缩。此外，对于儿童而言，捐赠器官池特别小，他们需要一部分成人肝脏。因此，对于那些生活质量极为差的儿童而言，等待合适的器官可能是多年，并且有可能在任何时间点发展代谢“危机”。此外，他们实际上只需要一小部分肝脏即可纠正缺陷。因此，取代整个肝脏有冗余，特别是鉴于资源受限和需求巨大。肝细胞是从不符合器官移植标准的肝脏中隔离的，因此它们是对原本无法使用的资源的极好利用。它们可以冷冻和存储，因此可以从架子上使用。肝细胞移植还可以保留患者肝功能的10-15％，即从原本不足的酶中提供足够的功能以纠正疾病。我们知道，在输注门静脉时，细胞会遇到先天免疫系统的攻击：血液开始凝块，蛋白质释放，吸引人体的防御细胞，并在肝脏到达肝脏之前被破坏植入和定居。传统的免疫抑制在内，包括类固醇不允许克服这一点，因此，超过90％的细胞在有机会植入之前被破坏了。 α-1抗胰蛋白酶（AAT）是一种在肝细胞中生产的蛋白质，具有一系列作用，可以阻止炎症的许多不良影响，而没有大多数常规免疫抑制剂的副作用，这会使人体容易受到感染和感染的攻击导致伤口愈合不佳。 AAT在全球临床试验中使用，在各种疾病中受炎症（例如1型糖尿病和缺血性心脏病）的影响。在糖尿病患者的胰岛移植领域也可以看到AAT作为免疫系统修饰剂的巨大成功，在这些胰岛移植领域，这些胰岛素产生的细胞也被移植到肝脏中。我们希望测试AAT在肝细胞移植领域的使用，因为我们认为这将导致肝脏中细胞的植入改善，从而更好地中等到长期的细胞功能，从而对那些人产生显着差异治疗。我们预测发生这种情况的机制将是抑制先天（即时）免疫系统，我们将在提供丢失的酶以及AAT对立即免疫的作用方面测量细胞的功能这些细胞被注入后的反应。尽管肝细胞移植是一个小领域，但它可能会导致对灾难性肝脏疾病的儿童改变生活的治疗。如果我们使用AAT证明了这种疗法的成功，这将进一步确认AAT作为一种有效且安全的免疫调节剂，在一般移植和其他炎症条件下。

项目成果

The Anti-Inflammatory Effect of Alpha-1 Antitrypsin in Hepatocyte Transplantation

Alpha-1抗胰蛋白酶在肝细胞移植中的抗炎作用

• DOI: 10.1097/01.tp.0000543016.63078.e3
• 发表时间: 2018
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: Lee C