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

肝细胞（肝细胞）移植是一种替代肝移植的某些条件。它涉及以微创方式将细胞移植到患者的肝脏中，通常通过供应肝脏的主静脉。这种治疗特别适合的患者是那些缺乏肝细胞中产生的特定酶的患者。这会导致有毒废物的积累和随之而来的不可逆的脑损伤。两个条件：Crigler-Najjar综合征（胆红素不能分解）和尿素循环缺陷（氨不能消除）由于这些有毒化合物的积累而导致严重的脑损伤。替换整个肝脏来替换缺失的酶是一种选择，但代价很高，因为这涉及大手术，通常伴有并发症，住院时间延长，如果移植失败，也没有退路。此外，对于儿童来说，供体器官库特别小，他们将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，并且有可能在任何时候发生代谢“危机”。此外，他们实际上只需要一小部分肝脏来纠正缺陷。因此，特别是考虑到有限的资源和巨大的需求，在替换整个肝脏方面存在冗余。肝细胞是从不符合器官移植标准的肝脏中分离出来的，因此它们是对一种不可用资源的极好利用。它们可以冷冻和储存，因此可以从货架上购买。肝细胞移植还允许患者保留自己的肝脏，同时提供10-15%的肝功能，即来自其他缺陷酶的足够功能以纠正疾病。我们知道，在输注到门静脉时，细胞会受到先天免疫系统的攻击：血液开始凝结，蛋白质释放，吸引身体的防御细胞，肝细胞在到达肝脏移植和定居之前被破坏。包括类固醇在内的常规免疫抑制剂无法克服这一点，因此，超过90%的细胞在有机会移植之前就被破坏了。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，这些副作用使身体容易受到感染的攻击并导致伤口愈合不良。AAT在全球范围内用于临床试验，用于各种受炎症影响的疾病，如1型糖尿病和缺血性心脏病。在糖尿病患者的胰岛移植领域中也已经看到AAT作为免疫系统调节剂的相当大的成功，其中这些胰岛素产生细胞也被移植到肝脏中。我们希望测试AAT在肝细胞移植领域中的应用，因为我们相信它将导致肝中细胞植入的改善，从而使细胞的中长期功能更好，与治疗的那些相比具有显著差异。我们预测，这种情况发生的机制将是先天（立即）免疫系统的抑制，我们将测量细胞在提供缺失酶方面的功能以及AAT对这些细胞输注后立即免疫反应的影响。虽然肝细胞移植是一个很小的领域，但它可以为患有毁灭性肝脏疾病的儿童带来改变生活的治疗。如果我们证明使用AAT的这种疗法的成功，这将进一步证明AAT在一般移植的背景下和在其他炎性病症中作为有效和安全的免疫调节剂的用途。

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.