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案。它涉及到将细胞移植到患者的肝脏中，通常是通过供应肝脏的主要静脉，以一种微创的方式。这种治疗特别适合的患者是那些缺少肝细胞中产生的一种特定酶的患者。这会导致有毒废物的积聚，从而造成不可逆转的脑损伤。两种这样的情况：Crigler-Najjar综合征(胆红素无法分解)和尿素循环缺陷(氨无法消除)，由于这些有毒化合物的积累而导致严重的脑损伤。替换整个肝脏以取代缺失的酶是一种选择，但代价高昂，因为这涉及大手术，通常会出现并发症，住院时间较长，如果移植失败，也没有后备选择。此外，捐赠者的器官池对儿童来说特别少，他们需要成人肝脏的一部分。因此，对于生活质量极差的儿童来说，等待合适的器官可能需要数年时间，他们可能在任何时候都有可能发展为新陈代谢危机。此外，他们实际上只需要一小部分肝脏就可以纠正这种不足。因此，替换整个肝脏是多余的，特别是考虑到有限的资源和巨大的需求。肝细胞是从不符合器官移植标准的肝脏中分离出来的，因此它们是对原本无法使用的资源的极好利用。它们可以冷冻和储存，因此可以从货架上买到。肝细胞移植还允许患者保存自己的肝脏，同时提供10%-15%的肝功能，即从原本缺乏的酶中获得足够的功能来纠正疾病。我们知道，在输注到门静脉时，细胞会遇到天然免疫系统的攻击：血液开始凝结，蛋白质被释放，吸引身体的防御细胞，肝细胞在到达肝脏植入和定居之前被摧毁。包括类固醇在内的常规免疫抑制不能克服这一点，因此，90%以上的细胞在有机会植入之前就被摧毁了。α-1抗胰蛋白酶(AAT)是一种在肝细胞中产生的蛋白质，具有一系列作用，可以阻断炎症的许多不良反应，而不会产生大多数传统免疫抑制剂的副作用，后者使身体容易受到感染的攻击，并导致伤口愈合不良。AAT在世界范围内用于临床试验，用于各种受炎症影响的条件下，如1型糖尿病和缺血性心脏病。AAT作为一种免疫系统调节剂在糖尿病患者的胰岛移植领域也取得了相当大的成功，这些产生胰岛素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应用，因为我们相信它将导致细胞在肝脏中的植入得到改善，从而更好地发挥细胞的中长期功能，使治疗后的情况发生显著变化。我们预测，这种情况发生的机制将是对先天(即时)免疫系统的抑制，我们将测量细胞供应缺失酶的功能，以及一旦这些细胞被注入，AAT对即时免疫反应的影响。尽管肝细胞移植是一个很小的领域，但它可以为患有毁灭性肝病的儿童带来改变生活的治疗。如果我们证明了使用AAT的这种治疗的成功，这将进一步证明AAT作为一种有效和安全的免疫调节剂，在一般的移植和其他炎症条件下使用。

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